3-(arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors

ABSTRACT

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

This application is a continuation application of Ser. No. 10/783,325,filed Feb. 20, 2004 which is a divisional application of Ser. No.10/256,879, filed Sep. 27, 2002, now U.S. Pat. No. 6,765,012 whichclaims priority under 35 U.S.C. §19(e)(1) to provisional applicationNos. 60/325,819 and 60/325,815, filed Sep. 27, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds capable of modulating,regulating and/or inhibiting tyrosine kinase signal transduction. Thepresent invention is also directed to methods of regulating, modulatingor inhibiting tyrosine kinases, whether of the receptor or non-receptorclass, for the prevention and/or treatment of disorders related tounregulated tyrosine kinase signal transduction, including cell growth,metabolic, and blood vessel proliferative disorders.

2. Description of the Related Art

Protein tyrosine kinases (PTKs) comprise a large and diverse class ofproteins having enzymatic activity. The PTKs play an important role inthe control of cell growth and differentiation.

For example, receptor tyrosine kinase mediated signal transduction isinitiated by extracellular interaction with a specific growth factor(ligand), followed by receptor dimerization, transient stimulation ofthe intrinsic protein tyrosine kinase activity and phosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic homeostasis, and responses tothe extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates which have a catalytic domain; and (2)substrates which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular).

The RTKs comprise a large family of transmembrane receptors with diversebiological activities. The intrinsic function of RTKs is activated uponligand binding, which results in phophorylation of the receptor andmultiple cellular substrates, and subsequently in a variety of cellularresponses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, theSrc subfamily of non-receptor tyrosine kinases is comprised of thelargest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. A more detailed discussion of non-receptor tyrosine kinasesis provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporatedherein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligands (U.S.Pat. No. 4,966,849), soluble receptors and antibodies (PCT ApplicationNo. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90:10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek,et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al,1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCTApplication Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808;U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. CancerRes. 35: 2268).

More recently, attempts have been made to identify small molecules whichact as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclicor heterocyclic aryl compounds (PCT Application No. WO 92/20642),vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have beendescribed generally as tyrosine kinase inhibitors. Styryl compounds(U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S.Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No.0 566 266 A1), seleoindoles and selenides (PCT Application No. WO94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO92/21660) and benzylphosphonic acid compounds (PCT Application No. WO91/15495) have been described as compounds for use as tyrosine kinaseinhibitors for use in the treatment of cancer.

The identification of effective small compounds which specificallyinhibit signal transduction by modulating the activity of receptor andnon-receptor tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation is therefore desirable and one objectof this invention.

Finally, certain small compounds are disclosed in U.S. Pat. Nos.5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful forthe treatment of diseases related to unregulated TKS transduction. Thesepatents are hereby incorporated by reference in its entirety for thepurpose of disclosing starting materials and methods for the preparationthereof, screens and assays to determine a claimed compound's ability tomodulate, regulate and/or inhibit cell proliferation, indications whichare treatable with said compounds, formulations and routes ofadministration, effective dosages, etc.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting tyrosine kinase signaltransduction. Such compounds are useful for the treatment of diseasesrelated to unregulated TKS transduction, including cell proliferativediseases such as cancer, atherosclerosis, restenosis, metabolic diseasessuch as diabetes, inflammatory diseases such as psoriasis and chronicobstructive pulmonary disease, vascular proliferative disorders such asdiabetic retinopathy, age-related macular degeneration and retinopathyof prematurity, autoimmune diseases and transplant rejection.

In one illustrative embodiment, the compounds of the present inventionhave the formula:

wherein R¹ is selected from the group consisting of halogen, NO₂, CN, C₁to C₄ alkyl and aryl, e.g. phenyl; R² is selected from the groupconsisting of hydrogen, C₁, to C₈ alkyl, COCH₃, CH₂CH₂OH, CH₂CH₂CH₂OHand phenyl; R is selected from the group consisting of D, halogen, C₁,to C₈ alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, SR², (CR⁷R⁸)_(c)C(O)OR²,C(O)N(R²)₂, (CR⁷R⁸)_(c)OR², HNC(O)R², HN—C(O)OR², (CR⁷R⁸)_(c)N(R²)₂, SO₂(CR⁷R⁸)N(R²)₂, OP(O)(OR²)₂, OC(O)OR², OCH₂O, HN—CH═CH, —N(COR²)CH₂CH₂,HC═N—NH, N═CH—S, O(CR⁷R⁸)_(d)—R⁶ and (CR⁷R⁸)_(c)—R⁶, —NR₂(CR⁷R⁸)_(d)R⁶wherein R⁶ is selected from the group consisting of halogen,3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate,N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl,morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl,N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl,1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4,5]decaninyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethyl)-1,3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N-BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran,ethanolamine and alkyl-substituted derivatives thereof and wherein whenc is 1 said CH₂ may be

and CH₂CH₂CH₂; provided said alkyl or phenyl radicals may be substitutedwith one or two halo, hydroxy or lower alkyl amino radicals wherein R⁷and R⁸ may be selected from the group consisting of H, F and C₁-C₄ alkylor CR⁷R⁸ may represent

-   a carbocyclic ring of from 3 to 6 carbons, preferably R⁷ and R⁸ are    H or CH₃;-   b is 0 or an integer of from 1 to 3;-   a is 0 or an integer of from 1 to 5, preferably 1 to 3;-   c is 0 or an integer of from 1 to 4, d is an integer of from 2 to 5;    the wavy line represents a E or Z bond and pharmaceutically    acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention R¹ is selected from the groupconsisting of H, i.e. b is 0; CH₃, F, Cl and phenyl.

Preferably, R is selected from the group consisting of CH₃, CH₂CH₃,OCH₃, OH, t-butyl, F, CN, C(O)NH₂, HN C(O)CH₃, CH₂C(O)OH, SO₂NH₂,C(O)OH, OCF₂H, isopropyl, C₂H₅OH, C(O)OCH₃, CH₂OH, NH—CH═CH, HC═N—N—H,N═CH—S, O(CR⁷R⁸)_(d)R⁶, (CR⁷R⁸)R⁶ and —NR² (CR⁷R⁸)_(d)R⁶, wherein R⁶ isselected from the group consisting of 3-fluoropyrrolidinyl,3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate,N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl,morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl,N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl,1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethyl)-1,3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N-BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl,4-aminomethyltetrahydropyranyl, ethanolamine and alkyl-substitutedderivatives thereof, e.g. R⁶ is morpholinyl or CH₂N(CH₃)₂.

More preferably, R is selected from the group consisting of m-ethyl,p-methoxy, p-hydroxy, m-hydroxy, p-cyano, m-C(O)NH₂, p-HNC(O)CH₃,p-CH₂C(O)OH, p-SO₂NH₂, p-CH₂OH, m-methoxy, p-CH₂CH₂OH, HNCH═CH, HC═N—NH,p-morpholinyl, N═CH—S, p-OCHF₂, p-COOH, p-CH₃, p-OCH₃, m-F,m-CH₂N(C₂H₃)₂, (CR⁷R⁸)_(c)R⁶, O(CR⁷R⁸)_(d)R⁶ and NR²(CR⁷R⁸)_(d)R⁶.

It is noted that R may represent a condensed ring that is attached tothe above phenyl ring at two positions. For example, as shown in Example23, below, CH₂CH₂CH₂ may be attached at the 3 and 4 (or m and p)positions of the phenyl ring.

Still more preferably, R is selected from the group consisting offluoro, methyl, (CR⁷R⁸)_(c)R⁶, O(CR⁷R⁸)_(d)R⁶ and NR²(CR⁷R⁸)_(d)R⁶wherein R⁶ is selected from dimethylamino, diethylamino,3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 3-pyridinyl, 4-pyridinyl,pyrrolidinyl, morpholinyl, piperazinyl, heptamethyleneiminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyranyl,N,N-diisopropylethylenediaminyl and 4-aminomethyltetrahydropyran.

In particular, the compounds of the present invention are selected fromthe compounds of Table 1, below. TABLE 1 Unsubstituted 4-Methyl &5-Chloro 3-[(Substituted Phenylamino)-methylene]-1,3-dihydro-indol-2-ones.

R Substitution Example # R¹ 2 3 4 5 6 1 H H H H H H 2 H H Br H H H 3 H HH Br H H 4 H Br H H H H 5 H H H Et H H 6 H H Et H H H 7 H H H OMe H H 8H H H CO₂Et H H 9 H Et H H H H 10 H H F Me H H 11 H Me F H H H 12 H H HOH H H 13 H H Cl OH H H 14 H Me H F H H 15 H H OH H H H 16 H H OMe H OMeH 17 H H H tBu H H 18 H H H Me H H 19 H H Me H Me H 20 H H Me Me H H 21H H F OMe H H 22 H H CF₃ H H H 23 H H —CH₂CH₂CH₂— H H 24 H F H Cl H H 25H H H CF₃ H H 26 H F H Me OCO₂Et H 27 H F H Me OCO₂CH₂C(CH₃)₃ H 28 H F HCl OH H 29 H H H CN H H 30 H H H CH₂CN H H 31 H H —CH═CH—NH— H H 32 H H—NH—N═CH— H H 33 H H H CONH₂ H H 34 H H H NHCOCH₃ H H 35 H H CH₂CO₂H H HH 36 H H H Cl H H

Unsubstituted, 4-methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 37 H H CO₂H Cl H H 38 H H H SO₂NH₂H H 39 H H H SO₂NHCOCH₃ H H 40 H H H N-morpholino H H 41 H H H OPh H H42 H H OMe OMe H H 43 H H —S—CH═N— H H 44 H H OH CO₂H H H 45 H H CF₃ ClH H 46 H H CF₃ H CF₃ H 47 H H CF₃ F H H 48 H H OH Me H H 49 H H OH OMe HH 50 H H H OCHF₂ H H 51 H H H OCF₃ H H 52 H H H iPr H H 53 H F H Me H H54 H H Me Cl H H 55 H H CF₃ OMe H H 56 H H CF₃ Me H H 57 5′-Cl H OMe H HH 58 4′-Me H H H H H 59 4′-Me H H OMe H H 60 4′-Me H OH H H H 61 4′-Me HOMe H OMe H 62 4′-Me H H Me H H 63 4′-Me H Me H Me H 64 5′-Cl H H OCHF₂H H 65 5′-Cl H OH OMe H H 66 5′-Cl H H OCF₃ H H 67 5′-Cl H Me OH H H 685′-Cl H —OCH₂O— H H 69 5′-Cl H Me Me H H 70 5′-Cl H H iPr H H 71 5′-Cl HOH Me H H 72 5′-Cl H H (CH₂)₂OH H H

Unsubstituted, 4-methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 73 5′-Cl H H OMe H H 74 5′-Cl H HH H H 75 5′-Cl H OMe H OMe H 76 5′-Cl H OH H H H 77 5′-Cl H H OH H H 785′-Cl H Me H Me H 79 5′-Cl H H Me H H 80 H H —OCH₂O— H H 81 H H CO₂H OHH H 82 H H H OEt H H 83 H H —N(COMe)—CH₂—CH₂— H H 84 H H H OPO(OH)₂ H H85 H H CO₂H CO₂H H H 86 H H H CO₂H H H 87 H H H (CH₂)₂OH H H 88 H H HCH₂OH H H 89 H H OMe CO₂CH₃ H H 90 4′-Me H —NH—N═CH— H H 91 4′-Me H FOMe H H 92 4′-Me H —S—CH═N— H H 93 4′-Me H OMe CO₂CH₃ H H 94 H H OMe H HH 95 4′-Me H Me Me H H 96 4′-Me H H OH H H 97 4′-Me H —CH═CH—NH— H H 984′-Me H H t-Bu H H 99 4′-Me H H CH₂OH H H 100 5′-Cl H H t-Bu H H 1015′-Cl H —S—CH═N— H H 102 5′-Cl H OMe OMe H H 103 5′-Cl H —NH—N═CH— H H104 5′-Cl OMe H Cl OMe H 105 5′-Cl H F OMe H H 106 5′-Cl H HN-morpholino H H 107 5′-Cl H H OEt H H 108 5′-Cl H CO₂H OH H H

Unsubstituted, 4-methyl & 5-Chloro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

Exam- R Substitution ple # R¹ 2 3 4 5 6 109 5′-Cl H CH₂NEt₂ OH H H 1105′-Cl H —CH═CH—NH— H H 111 5′-Cl H H CH₂OH H H 112 5′-Cl H Me iPr H H113 4′-Me H H CH₂CH₂OH H H 114 5′-Cl H H NHCOMe H H 115 5′-Cl H HCH₂CO₂H H H 116 5′-Cl H H SO₂NH₂ H H 117 4′-Me H OH OMe H H 118 4′-Me HCO₂H OH H H 119 4′-Me H H OCHF₂ H H 120 4′-Me H H OCF₃ H H 121 4′-Me HCF₃ OMe H H 122 4′-Me H H OEt H H 123 4′-Me H H iPr H H 124 4′-Me H—O—CH₂—O— H H 125 4′-Me H OH Me H H 126 4′-Me H OMe OMe H H 127 4′-Me EtH H H H 128 4′-Me H H CN H H 129 4′-Me H H CONH₂ H H 130 4′-Me H HNHCOCH₃ H H 131 4′-Me H H CH₂CO₂H H H 132 4′-Me H Me OH H H 133 H H MeOH H H 134 H H OH NHCO₂Et H H 135 4′-Me F H OMe H H 136 H H H SMe H H137 4′-Me H H SMe H H 138 5′-Cl H H SMe H H 139 H H H —CH₂CH₂CH₂CO₂H H H140 4′-Me H H —CH₂CH₂CH₂CO₂H H H 141 H H —CH₂CH₂CO₂H H H H 142 4′-Me H—CH₂CH₂CO₂H H H H 143 5′-Cl H —CH₂CH₂CO₂H H H H 144 H H H —CH₂CH₂CO₂H HH 145 4′-Me H H —CH₂CH₂CO₂H H H 146 5′-Cl H H —CH₂CH₂CO₂H H H

Unsubstituted, 4-methyl, 5-Chloro &5-Fluoro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 147 4′-Me H Et H H H 148 5′-Cl HEt H H H 149 5′-Cl H H Et H H 150 5′-Cl H H —CH₂CH₂CH₂CO₂H H H 151 4′-MeH H Et H H 152 5′-Cl H H —CN H H 155 4′-Me H OH CO₂H H H 156 H H HN(Me)₂ H H 157 H H H

H H 158 H H H

H H 159 H H H

H H 160 H H CH₂N(Et)₂ OH H H 161 4′-Me H CH₂N(Et)₂ OH H H 162 5′-F H—CH═CH—NH— H H 163 5′-F H —NH—N═CH— H H 164 5′-F H OH OMe H H 165 5′-F HH CH₂CH₂CO₂H H H 166 5′-F H H SO₂NH₂ H H 167 5′-F H H

H H 168 5′-F H H

H H 169 5′-F H H H H H 170 5′-F H H CONH₂ H H 171 5′-F H H SMe H H 1725′-F H F OMe H H 173 5′-F H —S—CH═N— H H 174 5′-F H H CH₂CO₂H H H 1755′-F H CH₂CH₂CO₂H H H H 176 5′-F H Et H H H

Unsubstituted, 4-methyl, 5-Chloro &5-Fluoro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 177 5′-F H OH H H H 178 5′-F H HCH₂OH H H 179 H H H

H H 180 H H H NH₂ H H 181 4′-Me H H NH₂ H H 182 H H CH(OH)CH₃ H H H 1834′-Me H CH(OH)CH₃ H H H 184 H H CH₂OH H H H 185 4′-Me H CH₂OH H H H 186H H NHCO₂t-Bu H H H 187 4′-Me H NHCO₂t-Bu H H H 188 H H H N(Et)₂ H H 1894′-Me H H N(Et)₂ H H 190 H H SO₂N(CH₂CH₂OH)₂ H H H 191 4′-Me HSO₂N(CH₂CH₂OH)₂ H H H 192 H H H SO₂NCH₂CH₂OH H H 193 H H SO₂NCH₂CH₂CH₂OHH H H 194 4′-Me H SO₂NCH₂CH₂CH₂OH H H H 195 H H CO₂H

H H 196 4′-Me H H

H H 197 4′-Me H H SO₂NCH₂CH₂OH H H 198 H H H OCH₂CH₂CH₂Cl H H 199 H H HOCH₂CH₂CH₂CH₂Cl H H 200 H H H OCH₂CH₂CH₂I H H 201 H H H OCH₂CH₂CH₂CH₂I HH 202 4′-Me D D D D D 203 H D D CO₂H D D 204 H D D NH₂ D D 205 4′-Me D DNH₂ D D

Unsubstituted, 4-methyl, 5-Chloro &5-Fluoro 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 206 H H H

H H 207 H H H OCH₂CH₂CH₂CH₂N(Et)₂ H H 208 H H H

H H 209 H H H

H H 210 4′-Me H NH₂ H H H 211 H H NH₂ H H H 212 H H NH₂ Me H H 213 4′-MeH NH₂ Me H H 214 H H H OCH₂CH₂CH₂N(Et)₂ H H 215 H H H

H H 216 H H H

H H 217 H H H

H H 218 H H H

H H 219 5′-F H H

H H 220 4′-Me H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 221 5′-F H H

H H 222 5′-F H H OMe H H 223 H D D D D D 224 H H H CH₂CO₂H H H 225 H H H

H H 226 H H H

H H 227 4′-Me H H

H H 228 6′-F H H

H H 229 6′-F H H

H H 230 6′-F H H

H H 231 4′-Me H H

H H 232 5′-Cl H H

H H 233 5′-F H H

H H 234 6′-F H H

H H 235 H H H

H H 236 5′-NO₂ H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 237 5′-CN H H

H H 238 5′-Me H H

H H 239 6′-F H H

H H 240 5′-F H H

H H 241 5′-Cl H H

H H 242 4′-Me H H

H H 243 6′-F H H

H H 244 5′-F H H

H H 245 5′-Cl H H

H H 246 4′-Me H H

H H 247 6′-F H H

H H 248 H H F

H H 249 4′-Me H F

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

Exam- Substitution ple # R¹ 2 3 4 5 6 250 6′-F H F

H H 251 H H H

H H 252 4′-Me H H

H H 253 6′-F H H

H H 254 H H H

H H 255 4′-F H H

H H 256 4′-Me H H

H H 257 4′-F H H

H H 258 5′-F H H

H H 259 6′-F H H

H H 260 5′-Cl H H

H H 261 4′-F H H

H H 262 5′-Cl H H

H H 263 5′-F H H

H H 264 4′-Me H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 265 H H H

H H 266 6′-F H H

H H 267 4′-F H H

H H 268 6′-(3- Methoxyphenyl) H H

H H 269 6′-(3- Methoxyphenyl) H H

H H 270 4′-Me H H

H H 271 6′-F H H

H H 272 H H H

H H 273 4′-F H H

H H 274 5′-F H H

H H 275 5′-Cl H H

H H 276 6′-(3- Methoxyphenyl) H H

H H 277 6′-(3- Methoxyphenyl) H H

H H 278 4′-Me H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 279 6′-F H H

H H 280 H H H

H H 281 4′-F H H

H H 282 5′-F H H

H H 283 5′-Cl H H

H H 284 H H H

H H 285 5′-Cl H H

H H 286 4′-Me H H

H H 287 4′-F H H

H H 288 5′-F H H

H H 289 6′-F H H

H H 290 H H H

H H 291 5′-Cl H H

H H 292 4′-Me H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Cyano, 5-Fluoro, 5-Nitro,6-Fluoro & 6-Aryl 3-[(SubstitutedPhenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 293 4′-F H H

H H 294 5′-F H H

H H 295 6′-F H H

H H 296 4′-Me H H

H H 297 H H H

H H 298 6′-F H H

H H 299 5′-Cl H H

H H 300 5′-F H H

H H 301 4′-F H H

H H 302 H H H

H H 303 4′-Me H H

H H 304 6′-F H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Fluoro &6-Fluoro3-[(Substituted Phenylamino)-methylene]-1,3-dihydro-indol-2-ones

R Substitution Example # R¹ 2 3 4 5 6 305 H H H

H H 306 H H H

H H 307 5′-Cl H H

H H 308 4′-Me H H

H H 309 4′-F H H

H H 310 5′-F H H

H H 311 6′-F H H

H H 312 H H H

H H 313 5′-Cl H H

H H 314 4′-Me H H

H H 315 4′-F H H

H H 316 5′-F H H

H H 317 6′-F H H

H H

Unsubstituted, 4-Fluoro, 4-methyl, 5-Chloro, 5-Fluoro &6-Fluoro3-[(Substituted Phenylamino)-methylene]-1,3-dihydro-indol-2-ones

Exam- R Substitution ple # R¹ 2 3 4 5 6 318 H H H

H H 319 5′-Cl H H

H H 320 4′-Me H H

H H 321 4′-F H H

H H 322 5′-F H H

H H 323 6′-F H H

H H

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient. Such acomposition is believed to modulate signal transduction by a tyrosinekinase, either by inhibition of catalytic activity, affinity to ATP orability to interact with a substrate.

More particularly, the compositions of the present invention may beincluded in methods for treating diseases comprising proliferation,fibrotic or metabolic disorders, for example cancer, fibrosis,psoriasis, atherosclerosis, arthritis, and other disorders related toabnormal vasculogenesis and/or angiogenesis, such as diabeticretinopathy.

The following defined terms are used throughout this specification:

“Me” refers to methyl.

“Et” refers to ethyl.

“tBu” refers to t-butyl.

“iPr” refers to i-propyl.

“Ph” refers to phenyl.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Alkyl” refers to a straight-chain, branched or cyclic saturatedaliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons.More preferably, it is a lower alkyl of from 1 to 7 carbons, mostpreferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl andthe like. The alkyl group may be optionally substituted with one or moresubstituents are selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkenyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon group containing at least one carbon-carbon double bond.Preferably, the alkenyl group has 1 to 12 carbons. More preferably it isa lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkenyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkynyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon containing at least one carbon-carbon triple bond.Preferably, the alkynyl group has 1 to 12 carbons. More preferably it isa lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkynyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkoxyl” refers to an “O-alkyl” group.

“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO₂, amine,thioether, cyano, alkoxy, alkyl, and amino.

“Alkaryl” refers to an alkyl that is covalently joined to an aryl group.Preferably, the alkyl is a lower alkyl.

“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.

“Heterocyclic aryl” refers to an aryl group having from 1 to 3heteroatoms as ring atoms, the remainder of the ring atoms being carbon.Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclicaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.

“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.

“Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl orhydrogen.

“Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylarylor hydrogen.

“Amine” refers to a —N(R″)R′″ group, wherein R″ and R′″ areindependently selected from the group consisting of alkyl, aryl, andalkylaryl.

“Thioether” refers to —S—R″, wherein R″ is alkyl, aryl, or alkylaryl.

“Sulfonyl” refers to —S(O)₂—R″″, where R″″ is aryl, C(CN)═C-aryl, CH₂CN,alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.

Also, alternatively the substituent on the aniline moiety is referred toas an o, m or p substituent or a 2, 3 or 4 substituent, respectively.(Obviously, the 5 substituent is also a m substituent and the 6substituent is an o substituent.

The present invention relates to compounds capable of regulating and/ormodulating tyrosine kinase signal transduction and more particularlyreceptor and non-receptor tyrosine kinase signal transduction.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and phosphorylation. Bindingsites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects and responses to theextracellular microenvironment).

It has been shown that tyrosine phosphorylation sites in growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Several intracellular substrate proteinsthat associate with receptor tyrosine kinases have been identified. Theymay be divided into two principal groups: (1) substrates which have acatalytic domain; and (2) substrates which lack such domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue. Differences in thebinding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each receptor tyrosine kinase is determined not only by its patternof expression and ligand availability but also by the array ofdownstream signal transduction pathways that are activated by aparticular receptor. Thus, phosphorylation provides an importantregulatory step which determines the selectivity of signaling pathwaysrecruited by specific growth factor receptors, as well asdifferentiation factor receptors.

Tyrosine kinase signal transduction results in, among other responses,cell proliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,arthritis and diabetic retinopathy (or other disorders related touncontrolled angiogenesis and/or vasculogenesis, e.g. maculardegeneration).

This invention is therefore directed to compounds which regulate,modulate and/or inhibit tyrosine kinase signal transduction by affectingthe enzymatic activity of the RTKs and/or the non-receptor tyrosinekinases and interfering with the signal transduced by such proteins.More particularly, the present invention is directed to compounds whichregulate, modulate and/or inhibit the RTK and/or non-receptor tyrosinekinase mediated signal transduction pathways as a therapeutic approachto cure many kinds of solid tumors, including but not limited tocarcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma,astrocytoma, melanoma and myoblastoma. Indications may include, but arenot limited to brain cancers, bladder cancers, ovarian cancers, gastriccancers, pancreas cancers, colon cancers, blood cancers, lung cancersand bone cancers.

Biological data for the compounds of the present invention was generatedby use of the following assays.

VEGF Stimulated Ca⁺⁺ Signal In vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of VEGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. HUVEC (humanumbilical vein endothelial cells) (Clonetics) were seeded in 96-wellfibronectin coated black-walled plates overnight at 37° C./5% CO₂. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 4 times (Original Cell Wash, Labsystems) to removeextracellular dye. Test compounds were reconstituted in 100% DMSO andadded to the cells to give a final DMSO concentration of 0.1%. Forscreening, cells were pre-incubated with test agents for 30 minutes, ata single concentration (10 μM) or at concentrations ranging from 0.01 to10.0 μM followed by VEGF stimulation (5 ng/mL). Changes in fluorescenceat 516 nm were measured simultaneously in all 96 wells using a cooledCCD camera. Data were generated by determining max-min fluorescencelevels for unstimulated, stimulated, and drug treated samples. IC₅₀values for test compounds were calculated from % inhibition of VEGFstimulated responses in the absence of inhibitor.

Protocol for KDR Assay:

KDR Assay:

The cytoplasmic domain of the human VEGF receptor (VEGFR-2) wasexpressed as a Histidine-tagged fusion protein following infection ofinsect cells using an engineered baculovirus. His-VEGFR-2 was purifiedto homogeneity, as determined by SDS-PAGE, using nickel resinchromatography. Kinase assays were performed in 96 well microtiterplates that were coated overnight with 30%1 g of poly-Glu-Tyr (4:1) in10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates wereincubated with 1% BSA and then washed four times with PBS prior tostarting the reaction. Reactions were carried out in 120 μL reactionvolumes containing 3.6 μM ATP in kinase buffer (50 mM Hepes buffer pH7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Test compounds werereconstituted in 100% DMSO and added to the reaction to give a finalDMSO concentration of 5%. Reactions were initiated by the addition 0.5ng of purified protein. Following a ten minute incubation at 25° C., thereactions were washed four times with PBS containing 0.05% Tween-20. 100μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugatewas diluted 1:10000 in PBS-Tween-20 and added to the wells for 30minutes. Following four washes with PBS-Tween-20, 100 μl ofO-phenylenediamine Dihydrochloride in Phosphate-citrate buffer,containing urea hydrogen peroxide, was added to the wells for 7 minutesas a colorimetric substrate for the peroxidase. The reaction wasterminated by the addition of 100 μl of 2.5N H₂SO₄ to each well and readusing a microplate ELISA reader set at 492 nm. IC₅₀ values for compoundinhibition were calculated directly from graphs of optical density(arbitrary units) versus compound concentration following subtraction ofblank values.

VEGF-induced Dermal Extravasation in Guinea Pig (Miles Assay). MaleHartley guinea pigs (300-600 g) were anesthetized with isofluorane,sheared, and given a single dose of drug or the respective vehicle. Theguinea pigs were dosed orally unless indicated otherwise in Table 3. Tenminutes prior to the end of drug treatment, guinea pigs wereanesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS(13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes,triplicate intradermal injections of 100 ng rhVEGF₁₆₅ in 100 μl PBS andof 100 μl PBS alone were administered on the flank. After 20 minutes,each animal was euthanized with Pentosol, and the skin containing theintradermal injection sites was removed for image analysis.

Using an analog video camera coupled to a PC, an image of eachtrans-illuminated skin sample was captured, and the integrated opticaldensity of each injection site was measured using ImagePro 4. For eachskin sample, the difference between the mean optical density of the VEGFsites and mean optical density of the PBS sites is the measure ofVEGF-induced EBD extravasation in that animal. These measured valueswere averaged per study group to determine the mean VEGF-induced EBDextravasation for each experimental condition, and the group means werethen compared to assess inhibition of VEGF-induced EBD extravasation inthe drug-treated groups relative to the vehicle-treated controls.

To determine the dose required for 50% inhibition (ID₅₀), the percentinhibition data was plotted as a function of oral dose, using the‘best-fit’ analysis within MicroSoft Excel software. The ID₅₀ value wasverified visually by using the plotted data (horizontal line from 50% yvalue, at intersection with best-fit line drop vertical line to x axis(dose)).

Laser-induced Choroidal Neovascularization (CNV) in Rat (CNV Assay). CNVwas induced and quantified in this model as previously described(Edelman and Castro. Exp. Eye Res. 2000; 71:523-533). On day 0, maleBrown Norway rats (200-300 g) were anesthetized with 100 mg/kg Ketamineand 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide.Using the blue-green setting of a Coherent Novus Argon Laser, 3 laserburns (90 mW for 0.1 s; 100 μm diameter) were given to each eye betweenthe retinal vessels around the optic nerve head. Rats were dosed withtest compounds in their indicated vehicles orally once daily.

On day 10, rats were sacrificed with 100% CO₂, and blood vessels werelabeled by vascular perfusion with 10 mg/ml FITC-dextran (MW 2×10⁶).Using an epifluorescence microscope (20×) coupled to a spot digitalcamera and a PC, images were obtained from the flat mounts of theRPE-choroid-sclera from each eye, and the area occupied byhyperfluorescent neovessels within each laser lesion was measured usingImagePro 4 software.

To determine the dose required for 50% inhibition (ID₅₀), the percentinhibition data was plotted as a function of oral dose, using the‘best-fit’ analysis within MicroSoft Excel software. The ID₅₀ value wasverified visually by using the plotted data (horizontal line from 50% yvalue, at intersection with best-fit line drop vertical line to x axis(dose)).

The results of said assays are set forth in Tables 2, 3 and 4 below,wherein NT means not tested. TABLE 2 Kinase Inhibition Data VEGFStimulated VEGF Stimulated Ca⁺⁺ signal assay Ca⁺⁺ signal assay KDR AssayExample # % inhibition @ 10 μM mean IC₅₀(μM) mean IC₅₀(μM) 1 92 4.05 NT2 −0.5 NT NT 3 3.50 NT NT 4 16.5 NT NT 5 77.280 1.82 0.48 6 90.06 1.840.52 7 94.50 0.95 0.69 8 9 NT NT 9 13.50 NT NT 10 46.00 10 NT 11 −14 NTNT 12 94.25 1.07 NT 13 −12.50 NT NT 14 −14.00 NT NT 15 93.70 0.19 0.9116 50 10    1.27 17 76.5 3.00 0.79 18 35.5 NT NT 19 14 NT NT 20 63 1.821.21 21 88 1.50 0.72 22 22.5 NT NT 23 42 NT NT 24 −13.5 NT NT 25 −1.5 NTNT 26 37.5 NT NT 27 −9 NT NT 28 32.5 NT NT 29 81.50 7.29 0.68 30 39.50NT NT 31 98.56 0.72 0.57 32 72.20 2.66 0.60 33 95.86 1.35 0.88 34 94.502.25 0.47 35 95.10 3.10 0.19 36 30.00 NT NT 37 −4.00 NT NT 38 92.08 1.450.50 39 −14.50 NT NT 40 96.71 0.25 0.25 41 16.00 NT NT 42 59.50 NT NT 4384.00 1.74 0.23 44 96.00 2.02 0.66 45 50.00 NT NT 46 −4.00 NT NT 47−2.50 NT NT 48 95.44 0.42 0.74 49 97.11 0.10 0.51 50 93.50 1.65 0.55 5145.50 NT NT 52 69.00 2.28 0.58 53 2.50 NT NT 54 40.50 NT NT 55 14.50 NTNT 56 21.00 NT NT 57 60.00 5.85 1.88 58 86.61 0.81 0.36 59 86.00 1.650.18 60 94.00 1.33 0.28 61 −4.50 NT NT 62 33.00 NT NT 63 −14.50 NT NT 6437.00 NT NT 65 95.50 1.10 0.53 66 18.50 NT NT 67 19.00 NT NT 68 −2.50 NTNT 69 −10.68 NT NT 70 25.00 NT NT 71 38.50 NT NT 72 81.50 1.56 0.43 7356.50 3.65 0.26 74 44.00 NT NT 75 −18.00 NT NT 76 55.50 NT NT 77 35.00NT NT 78 8.00 NT NT 79 −4.00 NT NT 80 3.50 NT NT 81 NT NT NT 82 NT 2.5 0.38 83 NT NT NT 84 11.50 NT NT 85 NT NT NT 86 48.50 NT NT 87 79.50 2.250.46 88 97.51 1.00 0.41 89 39.50 NT NT 90 97.81 0.42 0.22 91 93.50 3.020.24 92 69.00 1.77 0.15 93 51.50 6.62 0.63 94 92.50 3.88 0.64 95 14.00NT NT 96 97.00 1.68 0.20 97 96.50 1.86 0.20 98 47.50 NT NT 99 97.80 0.480.21 100 6.00 NT NT 101 22.00 NT NT 102 82.50 5.91 0.65 103 96.59 1.040.48 104 −14.50 NT NT 105 17.50 NT NT 106 96.59 0.60 0.23 107 41.50 NTNT 108 −14.50 NT NT 109 96.50 1.70 0.60 110 95.00 1.55 0.57 111 98.501.17 0.43 112 10.50 NT NT 113 97.52 035    0.20 114 88.96 1.93 0.92 11598.23 3.08 0.47 116 99.37 1.64 0.98 117 97.72 0.29 0.31 118 −26.96 NT NT119 89.28 1.34 0.53 120 12.67 NT NT 121 4.86 NT NT 122 71.71 1.54 0.37123 49.94 4.43 0.59 124 71..93 1.96 0.52 125 96.55 1.86 0.67 126 95.151.22 0.34 127 −11.79 NT NT 128 42.88 8.26 0.46 129 99.00 1.27 NT 13097.31 0.57 0.38 131 96.71 1.55 0.77 132 73 7.38 NT 133 73 4.91 NT 13483.09 7.39 1.12 135 27.98 NT 7.77 136 63.74 2.07 0.49 137 65.36 1.670.27 138 80.90 7.07 0.73 139 99.26 1.62 0.53 140 96.89 0.46 0.40 14192.56 2.96 0.51 142 99.27 4.16 0.21 143 66.92 7.61 0.52 144 96.51 2.700.46 145 98.73 0.59 0.19 146 98.38 2.07 0.51 147 71.57 5.49 0.15 14842.22 NT NT 149 17.67 NT 0.62 150 90.86 1.85 0.30 151 50.83 NT 0.46 15218.73 NT 10 155 97.15 2.60 0.40 156 95.36 0.83 0.51 157 97.89 0.23 0.25158 97.55 1.14 0.39 159 97.42 0.58 0.35 160 91.44 1.29 0.70 161 95.230.46 0.16 162 89.94 1.05 0.30 163 95.34 0.85 0.32 164 98.82 0.16 0.38165 99.33 1.34 0.36 166 49.17 NT 0.66 167 95.67 0.36 0.19 168 94.33 0.150.14 169 93.44 1.16 0.61 170 96.67 0.59 0.41 171 38.07 NT 0.43 172 93.331.40 0.69 173 94.54 1.48 0.52 174 76.40 6.02 0.84 175 38.03 NT 0.71 17667.88 2.54 0.80 177 98.17 0.74 0.75 178 98.78 1.06 0.53 179 97.35 0.640.31 180 98.33 1.03 0.44 181 97.73 0.49 0.35 182 99.29 0.95 1.65 18398.88 0.75 0.52 184 98.21 1.56 0.61 185 98.44 0.87 0.33 186 99.03 1.920.89 187 96.84 1.67 0.27 188 98.04 0.53 0.18 189 98.16 0.34 0.07 19054.11 9.99 6.96 191 98.65 2.41 0.70 192 98.66 1.53 0.59 193 81.51 4.772.47 194 96.91 2.67 0.66 195 91.12 4.67 0.96 196 73.10 0.77 0.05 19798.08 0.32 0.09 198 56.28 7.92 0.47 199 32.43 NT 0.29 200 75.19 3.480.74 201 44.15 NT 0.91 202 NT NT NT 203 NT NT NT 204 NT NT NT 205 NT NTNT 206 96.28 0.67 0.24 207 98.64 0.51 0.24 208 99.04 0.53 0.26 209 98.610.48 0.24 210 97.40 0.49 0.17 211 96.69 0.66 0.46 212 96.51 0.82 0.50213 94.97 0.65 0.15 214 97.35 0.35 0.33 215 96.66 0.67 0.34 216 95.310.57 0.34 217 97.68 0.86 0.28 218 98.12 0.44 0.17 219 97.38 0.62 0.22220 94.93 0.30 0.06 221 97.59 0.93 0.38 222 48.76 NT 0.47 223 NT NT NT224 56.18 6.31 2.27 225 95.70 0.56 0.29 226 97.97 0.70 0.28 227 85.900.17 0.05 228 97.25 0.15 0.08 229 97.19 0.23 0.11 230 96.39 0.05 0.08231 93.29 0.19 0.07 232 97.09 0.86 0.16 233 96.89 0.37 0.19 234 96.090.17 0.11 235 98.20 0.28 0.24 236 7.20 NT 0.97 237 36.44 NT 0.71 23898.39 0.78 0.06 239 97.65 0.19 0.15 240 98.32 0.41 0.23 241 95.81 1.010.13 242 95.82 0.13 0.07 243 95.63 0.10 0.11 244 95.98 0.20 0.19 24595.54 0.47 0.14 246 NT 0.36 0.09 247 NT 0.48 0.20 248 NT 0.71 0.63 249NT 0.38 0.07 250 NT 0.30 0.15 251 NT 0.46 0.14 252 NT 0.29 0.15 253 NT0.19 0.17 254 NT 0.47 0.50 255 NT 1.30 0.44 256 NT 0.67 0.19 257 NT 1.630.51 258 NT 0.72 0.56 259 NT 0.22 0.30 260 NT 0.88 0.30 261 NT 1.06 0.39262 NT 0.87 0.21 263 NT 0.47 0.36 264 NT 0.26 0.07 265 NT 0.53 0.61 266NT 0.12 0.17 267 NT 1.42 0.23 268 NT 10    0.08 269 NT 10    1.68 270 NT0.28 0.11 271 NT 0.10 0.13 272 NT 0.43 0.46 273 NT 1.07 0.33 274 NT 0.450.21 275 NT 0.62 0.13 276 NT 8.81 0.22 277 NT 10    0.25 278 NT 0.180.08 279 NT 0.17 0.16 280 NT 0.42 0.46 281 NT 0.73 0.32 282 NT 0.34 0.33283 NT 0.94 0.15 284 NT 0.25 0.25 285 NT 0.56 0.11 286 NT 0.13 0.04 287NT 0.62 0.11 288 NT 0.30 0.33 289 NT 0.42 0.26 290 NT 0.44 0.58 291 NT0.66 0.21 292 NT 0.14 0.09 293 NT 0.88 0.47 294 NT 0.40 0.38 295 NT 0.130.18 296 NT 0.16 0.14 297 NT 0.42 0.39 298 NT 0.10 0.34 299 NT 0.49 0.14300 NT 0.29 0.42 301 NT 0.77 0.27 302 NT 0.71 NT 303 NT 0.52 NT 304 NT0.12 NT 305 NT 0.55 0.31 306 NT 0.28 0.62 307 NT 0.65 0.27 308 NT 0.160.12 309 NT 0.68 0.23 310 NT 0.43 0.23 311 NT 0.12 0.10 312 NT 0.54 NT313 NT 0.99 NT 314 NT 0.32 NT 315 NT 1.54 NT 316 NT 0.59 NT 317 NT 0.17NT 318 NT NT NT 319 NT 0.95 NT 320 NT 0.33 NT 321 NT 1.18 NT 322 NT NTNT 323 NT NT NT

TABLE 3 Miles Assay Results Miles Assay Miles Assay Miles Assay MilesAssay Preincubation Miles Assay Example # dose (mg/kg) vehicle %inhibition period (h) ID₅₀ (mg/kg) 40 75 PEG400 100 18 75 corn oil 47 75micronized corn 52 oil 75 homogenized corn 40 oil 1 I.V. bolus in 0 0.520% methyl cyclodextrin 1 I.V. bolus in 0 1 20% methyl cyclodextrin 1I.V. bolus in 0 2 20% methyl cyclodextrin 10 43% methyl 6 1 cyclodextrin156 75 PEG400 (po) 100 157 75 PEG400 (po) 38 159 75 PEG400 91 167 75PEG400 31 179 75 PEG400 65 181 75 PEG400 38 206 75 corn oil 74 207 75corn oil 80 208 75 corn oil 32 209 75 PEG400 79 75 corn oil 84 211 75PEG400 38 214 75 PEG400 61 75 corn oil 78 215 75 PEG400 53 216 75 PEG40091 218 75 PEG400 99 75 corn oil 97 219 75 PEG400 28 220 75 PEG400 39 22975 PEG400 97 231 75 corn oil 93 234 75 corn oil 95 235 75 corn oil 99238 75 corn oil 60 239 75 corn oil 100 243 75 corn oil 100 247 75 cornoil 45 249 75 corn oil 29 250 75 corn oil 62 266 40 corn oil 82 271 40corn oil 98Legend:PEG = polyethylene glycoli.v. = intravenous dosage

TABLE 4 CNV Assay results CNV Assay CNV Assay CNV Assay CNV AssayExample # dose (mg/kg) vehicle % inhibition ID₅₀ (mg/kg) 40 50 (bid)corn oil 92 100 (sid) corn oil 74 40 (sid) PEG400 96 ˜20 100 (sid)PEG400 toxic 20 (sid) PEG400 54 20 (bid) PEG400 95 159 100 (sid) 10%DMAC, 41 10% NMP, 80% PEG400 209 80 (sid) corn oil 95 214 80 (sid) cornoil 85 218 80 (sid) corn oil 99 17 38.5 (sid) corn oil 68 9.3 (sid) cornoil 33 231 80 (sid) corn oil 85 234 80 (sid) corn oil 97 19 35 (sid)corn oil 76 8.6 (sid) corn oil 18 235 40 (sid) corn oil 63 239 40 (sid)corn oil 56Legendsid = once daily dosing;bid = twice daily dosing;DMAC = dimethylacetamide;NMP = N-methyl pyrolidinone;PEG = polyethylene glycol

As shown in Table 2, above, the compounds of Examples 1, 5, 6, 7, 12,15, 17, 21, 29, 31-35, 38, 40, 43, 44, 48-50, 52, 58-60, 65, 72, 73, 82,87, 88, 90-94, 96, 97, 99, 102, 103, 106, 109-111, 113-117, 119,122-126, 128-131, 134, 136, 138-147, 149-151, 155-159, 160-189, 191-201,206-222, 225-268, 270-314, 316, 317, 319, and 320 are preferred as theyshow either % inhibition of VEGF >79% or VEGF IC₅₀ <1.0 μM in either theVEGF stimulated Ca⁺⁺ signal assay or KDR assay.

As also can be seen in Table 2, above, the Compounds of Examples 7, 15,31, 40, 48, 49, 58, 88, 90, 99, 106, 113, 117, 130, 140, 145, 156, 157,159, 161, 163, 164, 167, 168, 170, 177, 179, 181, 183, 185, 188, 189,196, 197 and 206-221, 225-235, 238-240, 242-254, 256, 258-260, 262-266,270-272, 274, 275, 278-301 and 305-311 are more preferred as they showVEGF IC₅₀≦1.0 μM in both VEGF stimulated Ca⁺⁺ signal assay and KDRassays.

Finally, as shown in Tables 2, 3 and 4, the compounds of Examples 40,156, 157, 159, 167, 179, 181, 206-209, 211, 214-216, 218-220, 229, 231,234, 235, 238, 239, 243, 247, 249, 250, 266 and 271 are most preferredin that they show significant in-vivo activity and therefore would beeffective in oral administration.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1 Phenylaminomethylene-1,3-dihydro-indol-2-one

2.42 mL of ethylformate are combined with 1.33 gms of 1,3dihydro-indol-2-one in a solution of 21%, by weight, sodium formate inethanol. The resulting solution is allowed to stand at room temperaturefor 30 minutes and then refluxed for 30 minutes to yield a suspension.Once at room temperature the suspension was acidified to pH 1.0 with 10%HCl(aq), then 5 mL of H₂O was added. The resulting precipitate isfiltered and washed with H₂O (4×20 mL) to provide a mixture of E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as a solid.

E & Z 3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one is reacted with0.022 gms. of aniline by refluxing in tetrahydrofuran (1.2 mL) for 12hours to yield a quantitative amount (39 mg) of the named compound as asolid following concentration in vacuo, dilution with isopropanol andfiltration.

EXAMPLE 2 (3-Bromophenylamino)-methylene]-1,3-dihydro-indol-2-one

The named compound is prepared by substituting 3-bromoaniline foraniline in the reaction of Example 1.

The compounds of Example 3 through 198, 202-205, 210-213, 219-224,227-230 and 236-237 are prepared by substituting the appropriatesubstituted aniline for aniline, or the appropriate 4′-methyl or5′-fluoro or 5′-chloro or 6′-fluoro or 5′-nitro or 5′-cyano substituted1,3 dihydro-indol-2-one for 1,3 dihydro-indol-2-one in the reaction ofExample 1.

EXAMPLE 1793-{[4-(4-Pyrrolidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 207,3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand pyrrolidine are converted to the named compound

EXAMPLE 1983-{[4-(3-Chloro-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

A solution of3-[(4-hydroxy-phenylamino)-methylene]-0,1,3-dihydro-indol-2-one (0.945g, 3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg,1.5 equiv.) and 1-bromo-3-chloropropane (1.1 equiv.). The reactionmixture is heated to 40° C. for 3 h. The reaction mixture is partitionedbetween EtOAc and water. The organic layer is collected and washedsequentially with H₂O (1×), saturated aqueous NaHCO₃ solution (1×), andbrine (1×). The organic phase was dried and concentrated to give an oil.The oil was purified by preparative chromatography (silica gel; 1:1EtOAc:hexane) to give the named compound as a yellow solid (711 mg,58%).

EXAMPLE 1993-{[4-(4-Chloro-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

A solution of3-[(4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one (0.945 g,3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg, 1.5equiv.) and 1-bromo-4-chlorobutane (1.1 equiv.). The reaction mixture isheated to 40° C. for 3 h. The reaction mixture is partitioned betweenEtOAc and water. The organic layer is collected and washed sequentiallywith H₂O (1×), saturated aqueous NaHCO₃ solution (1×), and brine (1×).The organic phase is dried and concentrated to give a solid. The solidis triturated with MeOH and collected by filtration to give the namedcompound as yellow solid (600 mg, 47%).

EXAMPLE 2003-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

A solution of3-{[4-(3-Chloro-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one(45 mg, 0.137 mmol) and NaI (103 mg, 5 equiv.) in 1 mL acetone is heatedat 80° C. overnight. The reaction mixture is cooled to room temperatureand evaporated to dryness. The residue is dissolved in EtOAc and 1H₂O.The organic layer is collected and dried over anhydrous Na₂SO₄,filtered, and concentrated to give the named compound as yellow solid(100%).

EXAMPLE 2013-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described for Example 200,3-{[4-(4-Chloro-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-onewas converted to the named compound.

EXAMPLE 2063-{[4-(4-Morpholin-4-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 207,3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand morpholine are converted to the named compound.

EXAMPLE 2073-{[4-(4-Diethylamino-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

A 25 mL pressure tube is charged with3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one(75 mg, 0.173 mmol), diethylamine (2 mL) and the reaction mixture isheated at 50° C. for 3 h. The reaction mixture is cooled to roomtemperature and partitioned between EtOAc and H₂O. The organic layer iswashed with saturated aqueous NaHCO₃ solution, brine, and dried overanhydrous Na₂SO₄. The organic layer is collected by filtration andconcentrated to give a yellow solid. The solid is broken up in MeOH andcollected by filtration to give the named compound as a yellow solid.

EXAMPLE 2083-({4-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 207,3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand N-methylpiperazine are converted to the named compound.

EXAMPLE 2093-{[4-(4-Piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 207,3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand piperidine are converted to the named compound

EXAMPLE 2143-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand diethylamine are converted to the named compound.

EXAMPLE 2153-{[4-(3-Morpholin-4-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand morpholine are converted to the named compound.

EXAMPLE 2163-{[4-(3-Pyrrolidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand pyrrolidine are converted to the named compound.

EXAMPLE 2173-({4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

A solution of3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one(66 mg, 0.157 mmol) in 1 mL THF is treated with 1-methylpiperazine (37.2μL, 2.2 equiv.) and the resulting reaction mixture is heated at 50° C.for 4 h. The reaction mixture is cooled to room temperature andconcentrated under reduced pressure. The residue is partitioned betweenEtOAc and H₂O. The organic layer is collected and washed with saturatedaqueous NaHCO₃, brine, and dried over anhydrous Na₂SO₄. The yellow solidresidue obtained upon evaporation is broken up in 1:9 EtOAc:hexane andcollected by filtration to give the named compound as a yellow solid.

EXAMPLE 2183-{[4-(3-Piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand piperidine are converted to the named compound.

EXAMPLE 2253-{[4-(3-Thiomorpholin-4-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand thiomorpholine are converted to the named compound.

EXAMPLE 2263-{[4-(4-Thiomorpholin-4-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 207,3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand thiomorpholine are converted to the named compound.

EXAMPLE 2313-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one

To a solution of 4-(3-diethylamino-propoxy)-phenylamine (913 mg, 1.3equiv.) in THF (14 mL) is added4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (554 mg, 3.17 mmol)in one portion. The resulting reaction mixture is stirred and heated at72° C. overnight. The reaction solution is cooled to room temperatureand partitioned between EtOAc:H₂O. The organic layer is collected andwashed with saturated aqueous NaHCO₃ and dried over anhydrous Na₂SO₄.The organic phase is filtered and concentrated. The residue obtained istriturated with 1:4 EtOAc:hexane to give the named compound as a yellowsolid (625.8 mg, 52%).

EXAMPLE 231a Diethyl-[3-(4-nitro-phenoxy)-propyl]-amine

A solution of 3-diethylamino-1-propanol (2.97 mL, 20 mmol) in THF (40mL) at 0° C. is treated potassium tert-butoxide (2.36 g, 1.05 equiv.) inone portion. The reaction mixture is stirred at 0° C. for 5 min duringwhich time it becomes reddish brown. Neat 1-fluoro-4-nitrobenzene (2.82g, 1 equiv.) is added dropwise and the ice-bath is removed. The reactionmixture is stirred at room temperature for 15 min. The dark greenreaction mixture is quenched with ice-water (300 mL), and extracted withEtOAc (2×200 mL). The combined organic extracts are washed with water(2×300 mL) and brine (1×300 mL) and dried over anhydrous Na₂SO₄. Theoily brown residue obtained after evaporation, is purified bychromatography, (silica gel, 1:4 MeOH:CHCl₃) to give the named compoundas a brown oil (3.59 g, 71%).

EXAMPLE 231b 4-(3-Diethylamino-propoxy)-phenylamine

A solution of diethyl-[3-(4-nitro-phenoxy)-propyl]-amine (15.2 g, 60.4mmol) is dissolved in absolute ethanol (350 mL) and to this solution isadded hydrazine monohydrate (18 mL, 6 equiv.) followed by the additionof a small portion of Raney nickel. The reaction mixture is heated to50° C. with stirring for 3 h until all gas evolution has ceased. Thereaction mixture is filtered through celite to remove the Raney nickel.The filtrate is concentrated under reduced pressure to give the namedcompound as a greenish brown oil (quantitative). This material iscarried on in subsequent steps without purification.

EXAMPLE 2325-Chloro-3-{[4-(3-diethylamino-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-diethylamino-propoxy)-phenylamine (911 mg, 1.3 equiv.) and5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (617 mg, 3.16 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (577mg, 46%).

EXAMPLE 2333-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-diethylamino-propoxy)-phenylamine (161 mg, 1.3 equiv.) and5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100 mg, 0.56 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (88mg, 41%).

EXAMPLE 2343-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-diethylamino-propoxy)-phenylamine (5 g, 1.3 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (3.12 g, 17.4 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (4.1g, 61%).

EXAMPLE 2353-{[4-(2-Morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 1.26 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 3.45 gms. of N-(2-morpholin-4-yl-ethyl)-benzene-1,4-diamine intetrahydrofuran (34.02 mL) for 12 hours. Following concentration invacuo, dilution with hot isopropanol and filtration provides the namedcompound is isolated as a yellow solid in the amount of 1.731 gms.

N-(2-Morpholin-4-yl-ethyl)-benzene-1,4-diamine is prepared fromp-fluoronitrobenzene by the following method:

A mixture of 7.5 mL of p-fluoronitrobenzene, 10.25 mL2-morpholin-4-yl-ethylamine and 15 mL N,N-diisopropylamine in 36 mLdioxane is heated at 105° C. for 2 days. The reaction mixture is cooledto room temperature, diluted with dichloromethane (360 mL) and washedwith water (3×290 mL). Upon evaporation to dryness, the dichloromethanelayer yields the (2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amineproduct, which is recrystallized from methanol.

A suspension of 4.05 gms. of(2-morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine in 93 mL of ethanol isheated to 50° C. Once dissolution is achieved 4.8 mL hydrazinemonohydrate is added to the solution. A Raney nickel 2800 slurry inwater (approximately 3.5 mL) is added to the 50° C. solution dropwise,waiting after each addition for the bubbling to cease. Sufficientquantities of Raney nickel have been added when continued addition ofRaney nickel causes no further gas evolution. The reaction is thenmaintained at 50° C. for an additional hour, and subsequently is cooledto room temperature. The reaction mixture is filtered through a pad ofcelite (rinsing the pad with methanol). TheN-(2-morpholin-4-yl-ethyl)-benzene-1,4-diamine (3.45 gms.) is isolatedupon evaporation of the filtrate, and is subsequently used withoutpurification in the reaction of Example 235.

Examples 242, 243, 244, and 245 are prepared by substituting theappropriate 4′-methyl or 6′-fluoro or 5′-fluoro or 5′-chloro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one andN-(2-morpholin-4-yl-ethyl)-benzene-1,4-diamine, used for the preparationof Example 235, for aniline in the reaction of Example 1.

EXAMPLE 2384-Methyl-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.35 g, 2 mmol, 1equiv.) are reacted to give the named compound as a yellow solid (388mg, 49%).

EXAMPLE 238a 1-[3-(4-Nitro-phenoxy)-propyl]-piperidine

In a manner similar to that described in Example 231a,3-piperidino-propan-1-ol (1 g) is converted to the named compound as alight brown oil (1.85 g).

EXAMPLE 238b 4-(3-Piperidin-1-yl-propoxy)-phenylamine

In a manner similar to that described in Example 231b,1-[3-(4-nitro-phenoxy)-propyl]-piperidine (6.99 mmol) is converted tothe named compound as a brown oil (1.64 g).

EXAMPLE 2396-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.358 g, 2.00 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (465mg, 59%).

EXAMPLE 2405-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-piperidin-1-yl-propoxy)-phenylamine (0.57 g, 1.3 equiv.) and5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.363 g, 2 mmol, 1equiv.) are reacted to give the named compound as a yellow solid (379mg, 47%).

EXAMPLE 2415-Chloro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-piperidin-1-yl-propoxy)-phenylamine (550 mg, 1.3 equiv.) and5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (380 mg, 2.00 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (464mg, 58%).

EXAMPLE 2464-Methyl-3-{[4-(4-piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(4-Piperidin-1-yl-butoxy)-phenylamine (1.19 g, 1.1 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.79 g, 4.5 mmol, 1equiv.) are reacted to give the named compound as a yellow solid (0.97g, 53%).

EXAMPLE 246a 1-[4-(4-Nitro-phenoxy)-butyl]-piperidine

In a manner similar to that described in Example 231a,4-piperidino-butan-1-ol (36 mmol), is converted to the named compound asa light brown oil (8.61 g, 89%).

EXAMPLE 246b 4-(4-Piperidin-1-yl-butoxy)-phenylamine

In a manner similar to that described in Example 231b,1-[4-(4-nitro-phenoxy)-butyl]-piperidine (8.12 g, 29 mmol) is convertedto the named compound as a light greenish soft solid (6.46 g, 89%).

EXAMPLE 2476-Fluoro-3-{[4-(4-piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(4-piperidin-1-yl-butoxy)-phenylamine (400 mg, 1.1 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (263 mg, 1.47 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (435mg, 73%).

EXAMPLE 2483-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and3-hydroxymethylene-1,3-dihydro-indol-2-one (242 mg, 1.5 mmol, 1 equiv.)are reacted to give the named compound as a yellow solid (135 mg, 24%).

EXAMPLE 248a Diethyl-[3-(2-fluoro-4-nitro-phenoxy)-propyl]-amine

In a manner similar to that described in Example 231a,3,4-difluoronitrobenzene (6.7 mL, 60.6 mmol, 1 equiv.) and3-diethylamino-1-propanol (9 mL, 1 equiv.) are converted to the namedcompound as a brown oil (16.3 g).

EXAMPLE 248b 4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine

In a manner similar to that described in Example 23 lb,diethyl-[3-(2-fluoro-4-nitro-phenoxy)-propyl]-amine (16.3 g, 60.3 mmol)is converted to the named compound as a brown oil (12.4 g, 86%).

EXAMPLE 2493-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (263 mg, 1.5 mmol, 1equiv.) are reacted to give the named compound as a yellow solid (294mg, 49%).

EXAMPLE 2503-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (269 mg, 1.5 mmol, 1equiv.) are reacted to give the named compound as a yellow solid (195mg, 32%).

EXAMPLE 2513-[(4-Piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.025 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.036 gms. 4-piperidin-1-ylmethyl-phenylamine in tetrahydrofuran(1.5 mL) overnight. Following cooling to room temperture, solventevaporation in vacuo, trituration with isopropanol and filtration thereaction yields the named compound as a solid in the amount of 0.038gms.

Piperidin-1-ylmethyl-phenylamine is prepared from 4-nitro-benzoic acidby the following method:

A room temperature solution of 5.04 gms. 4-nitro-benzoic acid intetrahydrofuran (10 μL) is treated with 5.14 gms.1′,4′-carbonyl-diimidizole and immediately immersed in an ice bath. Thereaction mixture is stirred in the ice bath for 30 minutes, then it isallowed to warm to room temperature. Once at room temperature thereaction mixture is treated with 3 mL piperidine. The reaction mixtureis allowed to stir at room temperature ovenight. The reaction is thenmade basic with the addition of saturated aqueous sodium bicarbonatesolution, and the resulting mixture is extracted with ethyl acetate. Theorganics are separated, dried over anhydrous sodium sulfate, andsubsequently evaporated to dryness in vacuo. The crude product residueis then chromatographed by flash silica gel chromatography using 50%ethyl acetate in hexanes as the eluant. Following evaporation ofsolvent, 1-(4-nitrobenzoyl)piperidine is isolated as a white solid inthe amount of 5.87 gms.

1-(4-Nitrobenzoyl)piperidine (0.1125 gms.) is then dissolved intetrahydrofuran (1 mL) and slowly added dropwise to a 0° C., 1.0 Msolution (4 mL) of Borane in tetrahydrofuran. The reaction mixture ismaintained at 0° C. for 20 minutes following the completion of theaddition to the Borane/tetrahydrofuran solution. The reaction mixture isthen allowed to warm to room temperature, and is subsequently heated to60° C. using an oil bath. The reaction mixture is maintained at 60° C.overnight, then is cooled to room temperature, and quenched with theaddition of concentrated HCl (added until gas evolution stops). Thequenched reaction mixture is then extracted with ethyl acetate andwater. The organic layer is separated, and concentrated in vacuo, whilethe aqueous layer is separated and made basic with the addition ofaqueous 1M NaOH. The basic aqueous layer is then extracted with ethylacetate and the ethyl acetate layer from this extraction is concentratedin vacuo. The solids isolated from both concentrated ethyl acetatelayers are combined to yield 92 mg of 1-(4-nitro-benzyl)-piperidine as awhite-yellow solid.

1-(4-Nitro-benzyl)-piperidine (0.5052 gms.) is suspended in 25 mL of a1:1 (v:v) solution of acetic acid and water. The suspension is thentreated with 45 mL of an ˜10 wt. % solution of TiCl₃ in 20-30 wt. % HCl,dropwise. Over the course of the addition a color change from colorlessto purple to black ensues. The reaction mixture is immersed in a 60° C.oil bath overnight following the addition of TiCl₃. The reaction mixtureis then cooled to room temperature and made basic with the addition of a10% aqueous solution of NaOH. The basic reaction mixture is extractedwith chloroform, and the organic layer is dried over anhydrous sodiumsulfate. Following evaporation of the solvent the organic layer yields0.333 gms. of piperidin-1-ylmethyl-phenylamine.

EXAMPLE 2524-Methyl-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (754 mg, 1.2 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (530mg, 49%).

EXAMPLE 252a 1-[2-(4-Nitro-phenoxy)-ethyl]-piperidine

In a manner similar to that described in Example 231a,1-piperidine-ethanol (8.8 mL, 66 mmol, 1.1 equiv.) is converted to thenamed compound as a light brown solid (14.6 g, 97%).

EXAMPLE 252b 4-(2-Piperidin-1-yl-ethoxy)-phenylamine

In a manner similar to that described in Example 23 lb,1-[2-(4-nitro-phenoxy)-ethyl]-piperidine (5.0 g, 20 mmol) is convertedto the named compound as a light brown oil (4.4 g).

EXAMPLE 2536-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (737 mg, 1.2 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (745mg, 70%).

EXAMPLE 2543-{[4-(2-Piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (820 mg, 1.2 equiv.) and3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.)are reacted to give the named compound as a yellow solid (899 mg, 80%).

EXAMPLE 2554-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-piperidin-1-yl-propoxy)-phenylamine (610 mg, 1.3 equiv.) and4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (360 mg, 2 mmol, 1equiv.) are converted to the named compound as a yellow solid (625 mg,79%).

EXAMPLE 2564-Methyl-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.045 gms E &Z-3-hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, prepared bysubstituting 4′-methyl-1,3 dihydro-indol-2-one for 1,3dihydro-indol-2-one in the reaction of Example 1, with 0.064 gms.4-piperidin-1-ylmethyl-phenylamine, prepared as in the reaction ofExample 251, in tetrahydrofuran (1 mL) overnight. Following cooling toroom temperature, solvent evaporation in vacuo, trituration withisopropanol and filtration the reaction yields the named compound as asolid in the amount of 0.0463 gms.

Examples 257-260 are prepared by substituting the appropriate 4′-fluoroor 5′-fluoro or 6′-fluoro or 5′-chloro substituted1,3-dihydro-indol-2-one for the 1, 3-dihydro-indol-2-one and4-piperidin-1-ylmethyl-phenylamine (used in the preparation of Example251) for aniline in the reaction of Example 1.

EXAMPLE 2614-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol,1 equiv.) (4-Fluorooxindole may be prepared as described in Synthesis1991, 10, 871) are reacted to give the named compound as a yellow solid(542 mg, 63%).

EXAMPLE 2625-Chloro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (444 mg, 2.27 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (513mg, 57%).

EXAMPLE 2635-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (644mg, 74%).

EXAMPLE 2643-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one

In a manner similar to that describe in Example 231,4-(2-diethylamino-ethoxy)-phenylamine (713 mg, 1.2 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.86 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (237mg, 23%).

EXAMPLE 264a Diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine

In a manner similar to that described in Example 231a,N,N-diethylethanolamine (8.75 mL, 66 mmol, 1.1 equiv.) is converted tothe named compound as a brown oil (14.3 g).

EXAMPLE 264b 4-(2-Diethylamino-ethoxy)-phenylamine

In a manner similar to that described in Example 23 lb,diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (4.77 g, 20 mmol) is convertedto the named compound as a brown oil (4.16 g).

EXAMPLE 2653-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-diethylamino-ethoxy)-phenylamine (775 mg, 1.2 equiv.) and3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.)are reacted to give the named compound as a yellow solid (557 mg, 51%).

EXAMPLE 2663-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-Diethylamino-ethoxy)-phenylamine (697 mg, 1.2 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (399mg, 39%).

EXAMPLE 2673-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine (720 mg, 1.5 equiv.) and4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (358 mg, 2.00 mmol)are reacted to give the named compound as a yellow solid (541 mg, 67%).

EXAMPLE 2686-(3-Methoxy-phenyl)-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.020 gms E & Z3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one with0.021 gms 4-(4-methyl-piperazin-1-yl)-phenylamine in tetrahydrofuran(0.33 mL) for 2 days. Following cooling to room temperature, solventevaporation in vacuo, trituration with isopropanol (plus a littlechloroform) and filtration the reaction yields the named compound as asolid in the amount of 16.2 mg.

E & Z 3-Hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one isprepared in 5 steps from 4-Bromo-1-fluoro-2-nitro-benzene by thefollowing method:

4-Bromo-1-fluoro-2-nitro-benzene (5 gms.), 3.85 gms.3-methoxyphenylboronic acid and 22 mL of a 2M aqueous solution of sodiumcarbonate are suspended in 100 mL of a 1:1 (v:v) mix of toluene andethanol. The resulting suspension is then treated with 0.8 gms.tetrakis(triphenylphosphine)palladium (0) at room temperature. Thereaction mixture is then heated at reflux for 12 h. The reaction mixtureis subsequently concentrated in vacuo, and the resulting residue istaken up in ethyl acetate (200 mL). The ethyl acetate solution is thenwashed successively with water (2×200 mL), and brine (2×200 mL). Theorganic layer is then dried by filtering through phase separator paperand concentrated in vacuo to yield 7.19 gms. of crude product. The crudeproduct is then recrystallized from hot ethanol yielding4-fluoro-3′-methoxy-3-nitro-biphenyl as a yellow-white solid in theamount of 4.767 gms.

A room temperature DMSO (50 mL) suspension of a 60% dispersion of sodiumhydride in mineral oil (3.94 gms.) is treated dropwise with 10.41 mL ofdimethylmalonate. The suspension is then heated to 100° C. for 35minutes and subsequently treated with a solution of4-fluoro-3′-methoxy-3-nitro-biphenyl (4.6138 gms.) in DMSO (55 mL). Thereaction mixture is heated at 100° C. for an additional 1 h after whichit is cooled to room temperature, and quenched with the addition of asaturated aqueous solution of ammonium chloride (300 mL). The quenchedreaction mixture is then extracted with ethyl acetate (3×300 mL). Thecombined ethyl acetate washes are then washed with brine (1×500 mL),filtered through phase separator paper to dry the solution, and thenconcentrated in vacuo. The crude residue isolated is recrystallized fromisopropanol/ethyl acetate yielding2-(3′-methoxy-3-nitro-biphenyl-4-yl)-malonic acid dimethyl ester in theamount of 4.4023 gms.

2-(3′-Methoxy-3-nitro-biphenyl-4-yl)-malonic acid dimethyl ester (4.4023gms.) is suspended in 45 mL of 6N HCl and heated at 110° C. for 4 days.The reaction mixture is cooled to room temperature and the precipitateis collected by filtration. As the solid material is in rather largechunks, the solid purification is simplified by first dissolving thesolid chunks in an excess of hot methanol, and subsequentlyconcentrating the solution in vacuo to get a more manageable powder.This powder is then triturated with approximately 10 mL of methanol andfiltered yielding (3′-methoxy-3-nitro-biphenyl-4-yl)-acetic acid in theamount of 2.0120 gms.

A solution of (3′-Methoxy-3-nitro-biphenyl-4-yl)-acetic acid (2.0120gms.) in 35 mL methanol is treated with 0.3123 gms. of 10% palladium oncarbon. The resulting suspension is then stirred vigorously under anatmosphere of hydrogen at room temperature and atmospheric pressure for3 h. The reaction mixture is then filtered through a pad of celite, thefiltrate is treated with decolorizing charcoal and filtered a secondtime through celite. The filtrate is then concentrated in vacuo andpurified by trituration with isopropanol yielding 0.5736 gms. of6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one.

6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one (0.2282 gms.) is combinedwith 0.23 mL of ethylformate in 0.67 mL anhydrous ethanol, and istreated with a solution of 21%, by weight, sodium formate in ethanol(0.40 mL). The resulting solution is allowed to stand at roomtemperature for 30 minutes, and then is refluxed for 2 h to yield asuspension. Once at room temperature the suspension is acidified to pH1.0 with 10% HCl(aq), then diluted with 5 mL of H₂O. The resultingprecipitate was filtered and washed with H₂O (4×20 mL) to provide amixture of E & Z3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one, as asolid in the amount of 0.2064 gms.

EXAMPLE 269 6-(3-Methoxy-phenyl)-3-{[4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.020 gms E & Z3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one with0.020 gms. 4-morpholin-4-yl-phenylamine in tetrahydrofuran (0.33 mL) for2 days. Following cooling to room temperature, solvent evaporation invacuo, trituration with isopropanol and filtration the reaction yieldsthe named compound as a solid in the amount of 15.7 mg.

EXAMPLE 2704-Methyl-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231, (706 mg, 1.2equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg,2.86 mmol, 1 equiv.) are reacted to give the named compound as a yellowsolid (478 mg, 46%).

EXAMPLE 270a 1-[2-(4-Nitro-phenoxy)-ethyl]-pyrrolidine

In a manner similar to that described in Example 231a,1-(2-hydroxyethyl)-pyrroline (7.72 mL, 66 mmol, 1.1 equiv.) is convertedto the named compound as a brown oil (14.2 g).

EXAMPLE 270b 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine

In a manner similar to that described in Example 23 lb,1-[2-(4-nitro-phenoxy)-ethyl]-pyrrolidine (7.5 g, 30 mmol) is convertedto the named compound as a reddish oil (5.52 g, 89%).

EXAMPLE 2716-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (500mg, 48%).

EXAMPLE 2723-{[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2one

In a manner similar to that described in Example 231,4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (767 mg, 1.2 equiv.) and3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.)are reacted to give the named compound as a yellow solid (690 mg, 64%).

EXAMPLE 2734-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol,1 equiv.) to give the named compound as a yellow solid (790 mg, 77.0%).

EXAMPLE 2745-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (705mg, 69%).

EXAMPLE 2755-Chloro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (632 mg, 1.2 equiv.) and5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.56 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (775mg, 79%).

EXAMPLE 2766-(3-Methoxy-phenyl)-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.020 gms E & Z3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (seeexample 268) with 0.0375 gms 4-(3-piperidin-1-yl-propoxy)-phenylamine(used in the preparation of Example 218) in tetrahydrofuran (0.33 mL)for 36 h. Following cooling to room temperature, solvent evaporation invacuo, trituration with isopropanol and filtration the reaction yieldsthe named compound as a solid in the amount of 16.8 mg.

EXAMPLE 2773-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.020 gms E & Z3-Hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (seeexample 268) with 0.0327 gms 4-(3-diethylamino-propoxy)-phenylamine(used in the preparation of Example 214) in tetrahydrofuran (0.33 mL)for 36 h. Following cooling to room temperature, solvent evaporation invacuo, trituration with ethyl acetate/(min) hexanes and filtration thereaction yields the named compound as a solid in the amount of 9.0 mg.

EXAMPLE 2784-Methyl-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (603 mg, 1.2 equiv.) and4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.28 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (439mg, 51%).

EXAMPLE 278a 1-Methyl-3-(4-nitro-phenoxymethyl)-piperidine

In a manner similar to that described in Example 231a,1-methyl-3-piperidinemethanol (8.53 g, 66 mmol, 1.1 equiv.) is convertedto the named compound as a brown oil (11.5 g, 77%).

EXAMPLE 278b 4-(1-Methyl-piperidin-3-ylmethoxy)-phenylamine

In a manner similar to that described in Example 23 lb,1-Methyl-3-(4-nitro-phenoxymethyl)-piperidine (7.5 g, 30 mmol) isconverted to the named compound as a light brown solid (4.82 g, 73%).

EXAMPLE 2796-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (466mg, 55%).

EXAMPLE 2803-{[4-(1-Methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (656 mg, 1.2 equiv.) and3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.48 mmol, 1 equiv.)are reacted to give the named compound as a yellow solid (732 mg, 81%).

EXAMPLE 2814-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol,1 equiv.) are reacted to give the named compound as a yellow solid (576mg, 68%).

EXAMPLE 2825-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (688 mg,1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400mg, 2.23 mmol, 1 equiv.) with the addition of anhydrous Et₃N (2.25equiv.) are reacted to give the named compound as a yellow solid (657mg, 77%).

EXAMPLE 2835-Chloro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 231,4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (158 mg,1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100mg, 0.51 mmol, 1 equiv.) with the addition of anhydrous Et₃N (2.11equiv.) are reacted to give the named compound as a yellow solid (100mg, 49%).

EXAMPLE 2843-{[4-(2-Piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0505 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.085 gms. 4-(2-piperidin-1-yl-ethyl)-phenylamine intetrahydrofuran (1.0 mL) overnight. Following cooling to roomtemperture, solvent evaporation in vacuo, trituration with isopropanoland filtration the reaction yields the named compound in the amount of66 mg.

4-(2-Piperidin-1-yl-ethyl)-phenylamine is prepared from(4-Nitro-phenyl)-acetic acid by the following method:

A room temperature solution of 2.53 gms. (4-Nitro-phenyl)-acetic acid intetrahydrofuran (10 mL) is treated with 2.44 gms.1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath. Thereaction mixture is stirred in the ice bath for 30 minutes then it isallowed to warm to room temperature. Once at room temperature thereaction mixture is treated with 1.21 mL piperidine, and then is stirredovernight at room temperature. The reaction is then made basic with theaddition of saturated aqueous sodium bicarbonate, and the resultingmixture is extracted with ethyl acetate. The organics are separated,dried over anhydrous sodium sulfate, filtered, and subsequentlyevaporated to dryness in vacuo. The crude product residue is thenchromatographed by flash silica gel chromatography using 50% ethylacetate in hexanes as the eluant. Following evaporation of solvent,2-(4-nitro-phenyl)-1-piperidin-1-yl-ethanone is isolated as a whitesolid in the amount of 3.18 gms.

2-(4-Nitro-phenyl)-1-piperidin-1-yl-ethanone (1.24 gms.) is thendissolved in tetrahydrofuran (5 mL), and slowly added dropwise to a 0°C., 1.0M solution (35 mL) of Borane in tetrahydrofuran. The reactionmixture is maintained at 0° C. for 20 minutes following the completionof the addition to the Borane/tetrahydrofuran solution. The reactionmixture is then allowed to warm to room temperature, and is subsequentlyrefluxed using an oil bath. The reaction mixture is maintained atrefluxing temperature overnight, then cooled to 0° C. and quenched withthe addition of concentrated HCl (added until fizzing stops). Thequenched reaction mixture is then extracted with ethyl acetate andwater. The organic layer is then separated, dried over sodium sulfateand concentrated in vacuo. The solid isolated is then triturated withhexanes and a little ethyl acetate to yield 0.7563 gms. of1-[2-(4-nitro-phenyl)-ethyl]-piperidine as a white solid followingfiltration.

1-[2-(4-Nitro-phenyl)-ethyl]-piperidine (0.1178 gms.) is suspended in4.5 mL of a 1:1 (v:v) solution of acetic acid and water. The suspensionis then immersed in a 65° C. oil bath and treated in dropwise fashionwith 9 mL of an ˜10 wt. % solution of TiCl₃ in. 20-30 wt. % HCl. Overthe course of the addition a color change from colorless to purple toblack ensues. The reaction mixture is maintained in the 65° C. oil bathovernight following the addition of TiCl₃. The reaction mixture is thencooled to 0° C., and made basic with the addition of a 10% aqueoussolution of NaOH. The basic reaction mixture is then extracted withchloroform. The emmulsion that forms is filtered through glass wool,re-extracted with chloroform, and then dried over anhydrous sodiumsulfate. Following evaporation of the solvent the residue ischromatographed by flash silica gel chromatography (10% methanol inchloroform) to yield 60 mg of 4-(2-piperidin-1-yl-ethyl)-phenylamine.

EXAMPLE 2864-Methyl-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.055 gms. E &Z-3-Hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared inthe reaction of Example 1, with 0.085 gms.4-(2-piperidin-1-yl-ethyl)-phenylamine (used in the preparation ofExample 284) in tetrahydrofuran (1 mL) overnight. Following cooling toroom temperture, solvent evaporation in vacuo, trituration withisopropanol and filtration the reaction yields the named compound as asolid in the amount of 38 mg.

Examples 285 and 287-289 are prepared by substituting the appropriate5′-chloro or 4′-fluoro or 5′-fluoro or 6′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and4-(2-piperidin-1-yl-ethyl)-phenylamine (used in the preparation ofExample 284) for aniline in the reaction of Example 1.

EXAMPLE 2903-[(4-Morpholin-4-ylmethyl-phenylamino)-methylene-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.051 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.085 gms. 4-morpholin-4-ylmethyl-phenylamine in tetrahydrofuran(2.0 mL) overnight. Following cooling to room temperture, solventevaporation in vacuo, trituration with isopropanol and filtration thereaction yields the named compound as a solid in the amount of 0.070gms.

4-Morpholin-4-ylmethyl-phenylamine is prepared from 4-Nitro-benzoic acidby the following method:

A room temperature solution of 2.49 gms. 4-nitro-benzoic acid intetrahydrofuran (15 mL) is treated with 2.44 gms.1′,1′-carbonyl-diimidizole, and immediately immersed in an ice bath. Thereaction mixture is stirred in the ice bath for 30 minutes then it isallowed to warm to room temperature. Once at room temperature thereaction mixture is treated with 1.5 mL piperidine. The reaction mixtureis allowed to stir at room temperature ovenight. The reaction is thenmade basic with the addition of saturated aqueous sodium bicarbonatesolution, and the resulting mixture is extracted with ethyl acetate. Theorganics are separated, dried over anhydrous sodium sulfate andsubsequently evaporated to dryness in vacuo. The crude product residueis then chromatographed by flash silica gel chromatography using 50%ethyl acetate in hexanes as the eluant. Following evaporation ofsolvent, 1-(4-nitrobenzoyl)morpholine is isolated as a white solid inthe amount of 1.679 gms.

1-(4-Nitrobenzoyl)morpholine (1.1219 gms.) is then dissolved intetrahydrofuran (6 mL) and slowly added dropwise to a 0° C., 1.0Msolution (30 mL) of Borane in tetrahydrofuran. The reaction mixture ismaintained at 0° C. for 20 minutes following the completion of theaddition to the Borane/tetrahydrofuran solution. The reaction mixture isthen allowed to warm to room temperature, and is subsequently heated toreflux using an oil bath. The reaction mixture is maintained atrefluxing temperature overnight, then cooled to room temperature andquenched with the addition of concentrated HCl (added until gasevolution stops). The quenched reaction mixture is then extracted withethyl acetate and water. The organic layer is then separated andconcentrated in vacuo to yield 0.6650 gms. of1-(4-nitro-benzyl)-morpholine as a yellow solid.

1-(4-Nitro-benzyl)-morpholine (0.6446 gms.) is suspended in 15 mL of a1:1 (v:v) solution of acetic acid and water. The suspension is thenheated with a heat gun until a homogeneous solution forms. The solutionis then treated with 35 mL of an ˜10 wt. % solution of TiCl₃ in 20-30wt. % HCl, dropwise. Over the course of the addition a color change fromcolorless to purple to black ensues. The reaction mixture is immersed ina 60° C. oil bath overnight following the addition of TiCl₃. Thereaction mixture is then cooled to room temperature and made basic withthe addition of a 10% aqueous solution of NaOH. The basic reactionmixture is then extracted with chloroform four times and the combinedorganic layers are dried over anhydrous sodium sulfate. Followingfiltration and evaporation of the solvent in vacuo, the organic layeryields 0.5112 gms. 4-morpholin-4-ylmethyl-phenylamine.

EXAMPLE 2924-Methyl-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.056 gms E &Z-3-hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, prepared bysubstituting 4′-methyl-1,3 dihydro-indol-2-one for 1,3dihydro-indol-2-one in the reaction of Example 1, with 0.085 gms.4-morpholin-4-ylmethyl-phenylamine, prepared as in the reaction ofExample 290, in tetrahydrofuran (2.0 mL) overnight. Following cooling toroom temperature, solvent evaporation in vacuo, trituration withisopropanol, and filtration the reaction yields the named compound as asolid in the amount of 12 mg.

Examples 291, and 293-295 are prepared by substituting the appropriate5′-chloro or 4′-fluoro or 5′-fluoro or 6′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and4-morpholin-4-ylmethyl-phenylamine, used in the preparation of Example290, for aniline in the reaction of Example 1.

EXAMPLE 2964-Methyl-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by substituting4-methyl-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one andN-(3-morpholin-4-yl-propyl)-benzene-1,4-diamine (used for thepreparation of Example 290) for aniline in the reaction of Example 1.

EXAMPLE 2973-{[4-(3-Morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydroindol-2-one

The named compound is prepared by refluxing 0.336 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.730 gms. N-(3-morpholin-4-yl-propyl)-benzene-1,4-diamine intetrahydrofuran (12.5 mL) for 24 hours to yield the named compound as asolid in the amount of 0.513 gms. following concentration in vacuo,recrystallization with hot isopropanol and filtration.

N-(3-Morpholin-4-yl-propyl)-benzene-1,4-diamine is prepared fromp-fluoronitrobenzene by the following method:

A mixture of 4.85 mL of p-fluoronitrobenzene, 6.0 gms.2-morpholin-4-yl-ethylamine and 8.69 mL N,N-diisopropylamine in 20.8 mLdioxane is heated at 105° C. for 2 days. The reaction mixture is cooledto room temperature, evaporated to dryness, and recrystallized from hotisopropanol yielding the(3-morpholin-4-yl-propyl)-(4-nitro-phenyl)-amine product in the amountof 5.30 gms.

A suspension of 5.00 gms. of(3-morpholin-4-yl-propyl)-(4-nitro-phenyl)-amine in 110 mL of ethanol isheated to 50° C. Once dissolution is achieved 5.49 mL hydrazinemonohydrate is added to the solution. A Raney nickel slurry in water isadded to the 50° C. solution dropwise, waiting after each addition forthe bubbling to cease. Sufficient quantities of Raney nickel have beenadded when continued addition of Raney nickel causes no further gasevolution. The reaction is then maintained at 50° C. for an additionalhour, and subsequently is cooled to room temperature. The reactionmixture is filtered through a pad of celite (rinsing the pad withmethanol). N-(3-Morpholin-4-yl-propyl)-benzene-1,4-diamine (4.39 gms.)is isolated. upon evaporation of the filtrate, and is subsequently usedwithout purification in the reaction of Example 297.

Example 298-301 are prepared by substituting the appropriate. 6′-fluoroor 5′-chloro or 5′-fluoro or 4′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one andN-(3-morpholin-4-yl-propyl)-benzene-1,4-diamine (used in the preparationof Example 297) for aniline in the reaction of Example 1.

EXAMPLE 3023-({4-[3-(4-Methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.135 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.035 gms.N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine intetrahydrofuran (1 mL) for 24 hours. Following concentration in vacuoand recrystallization from hot isopropanol and filtration the namedcompound is isolated as a yellow solid in the amount of 0.0151 gms.

N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine was preparedfrom p-fluoronitrobenzene by the following method:

A mixture of 4.44 mL of p-fluoronitrobenzene, 6 gms.3-(4-methyl-piperazin-1-yl)-propylamine and 6.65 mL N,N-diisopropylaminein 19 mL dioxane is heated at 105° C. for 2 days. The reaction mixtureis cooled to room temperature, evaporated to dryness, and recrystallizedfrom hot isopropanol yielding[3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in theamount of 0.1385 gms.

A suspension of 0.1385 gms. of[3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in 3 mL ofethanol is heated to 50° C. Once dissolution is achieved 0.144 mLhydrazine monohydrate is addded to the solution. A Raney nickel slurryin water is added to the 50° C. solution dropwise, waiting after eachaddition for the gas evolution to cease. Sufficient quantities of Raneynickel have been added when continued addition of Raney nickel causes nofurther gas evolution. The reaction is then maintained at 50° C. for anadditional hour, and subsequently is cooled to room temperature. Thereaction mixture is filtered through a pad of celite (rinsing the padwith methanol).N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (0.116 gms.)is isolated upon evaporation of the filtrate, and is subsequently usedwithout purification in the reaction of Example 302.

EXAMPLE 3034-Methyl-3-({4-[3-(4-methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

The named compound is prepared by substituting4-methyl-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one andN-[3-(4-methyl-piperazin-1-yl)- propyl]-benzene-1,4-diamine (used forthe preparation of Example 302) for aniline in the reaction of Example1.

EXAMPLE 3046-Fluoro-3-({4-[3-(4-methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

The named compound is prepared by substituting6-fluoro-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one andN-[3-(4-methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (used for thepreparation of Example 302) for aniline in the reaction of Example 1.

EXAMPLE 3053-({4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one

In a manner similar to that described in Example 217,3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-oneand 3-fluoro-pyrrolidine hydrochloride (226 mg, 1.2 equiv.) (prepared bythe method of Giardina, G et al, Synlett (1995), (1), 55-7) areconverted to the named compound as a slightly brownish yellow solid (258mg, 45%).

EXAMPLE 3063-{[4-(2-Morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0644 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.1088 gms. 4-(2-morpholin-4-yl-ethyl)-phenylamine intetrahydrofuran (1.5 mL) overnight. Following cooling to roomtemperture, solvent evaporation in vacuo, trituration with isopropanoland filtration the reaction yields the named compound in the amount of91.1 mg.

4-(2-Morpholin-4-yl-ethyl)-phenylamine is prepared from(4-nitro-phenyl)-acetic acid by the following method:

A room temperature solution of 1.8839 gms. (4-Nitro-phenyl)-acetic acidin tetrahydrofuran (5 mL) is treated with 1.8069 gms.1′,1′-carbonyl-diimidizole. The reaction mixture is stirred for 1 h. Thereaction mixture is then treated with 1.0 mL morpholine. The reaction isheated overnight at 35° C. The reaction is then allowed to cool to roomtemperature, and is made basic with the addition of saturated aqueoussodium bicarbonate. The resulting mixture is extracted with ethylacetate. The aqueous layer is re-extracted four more times with ethylacetate. The combined organics are evaporated to dryness in vacuo. Thecrude product residue is then chromatographed by flash silica gelchromatography using 60% ethyl acetate in hexanes as the eluant.Following evaporation of solvent,1-morpholin-4-yl-2-(4-nitro-phenyl)-ethanone is isolated as a whitesolid in the amount of 1.4009 gms.

1-Morpholin-4-yl-2-(4-nitro-phenyl)-ethanone (1.4009 gms.) is thendissolved in tetrahydrofuran (7.5 mL) and slowly added dropwise to a 0°C., 1.0M solution (40 mL) of Borane in tetrahydrofuran. The reactionmixture is maintained at 0° C. for 30 minutes following the completionof the addition to the Borane/tetrahydrofuran solution. The reactionmixture is then allowed to warm to room temperature, and is subsequentlyrefluxed using an oil bath. The reaction mixture is maintained atrefluxing temperature overnight, then cooled to 0° C., and quenched withthe addition of concentrated HCl (added until fizzing stops). Thequenched reaction mixture is then warmed to room temperature, andextracted with ethyl acetate and water. The organic layer is thenseparated, dried over sodium sulfate and concentrated in vacuo. Thesolid isolated is then chromatographed by flash silica gelchromatography using 30% ethyl acetate in hexanes as the eluant to yield0.7993 gms. of 4-[2-(4-nitro-phenyl)-ethyl]-morpholine as a white solid.

4-[2-(4-Nitro-phenyl)-ethyl]-morpholine (0.7993 gms.) is suspended in 30mL of a 1:1 (v:v) solution of acetic acid and water. The suspension isthen immersed in a 60° C. oil bath and treated in dropwise fashion with40 mL of an ˜10 wt. % solution of TiCl₃ in 20-30 wt. % HCl. The reactionmixture is maintained in the 60° C. oil bath overnight following theaddition of TiCl₃. The reaction mixture is then cooled to 0° C., and ismade basic with the addition of a 10% aqueous solution of NaOH. Thebasic reaction mixture is then extracted with chloroform. The emmulsionthat forms is filtered through glass wool, re-extracted with chloroformand then dried over anhydrous sodium sulfate. Following evaporation ofthe solvent the residue is chromatographed by flash silica gelchromatography (10% methanol in chloroform) which then yielding 0.6528gms. of 4-(2-morpholin-4-yl-ethyl)-phenylamine.

EXAMPLE 3084-Methyl-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0707 gms. E &Z-3-Hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared inthe reaction of Example 1, with 0.1088 gms.4-(2-morpholin-4-yl-ethyl)-phenylamine (used in the preparation ofExample 306) in tetrahydrofuran (1.5 mL) overnight. Following cooling toroom temperture, solvent evaporation in vacuo, trituration withisopropanol and filtration the reaction yields the named compound as asolid in the amount of 77 mg.

Examples 307 and 309-311 are prepared by substituting the appropriate5′-chloro or 4′-fluoro or 5′-fluoro or 6′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and4-(2-morpholin-4-yl-ethyl)-phenylamine (used in the preparation ofExample 306) for aniline in the reaction of Example 1.

EXAMPLE 3123-{[4-(4-Morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0687 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.131 gms. 4-(4-morpholin-4-yl-butyl)-phenylamine intetrahydrofuran (1.5 mL) overnight. Following cooling to roomtemperture, solvent evaporation in vacuo, trituration with isopropanoland filtration the reaction yields the named compound in the amount of0.1165 gms.

4-(4-Morpholin-4-yl-butyl)-phenylamine is prepared from4-(4-nitro-phenyl)-butyric acid by the following method:

A room temperature solution of 1.1180 gms. 4-(4-nitro-phenyl)-butyricacid in tetrahydrofuran (3 mL) is treated with 0.9052 gms.1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensityof the reaction. The reaction mixture is stirred for 1 h. The reactionmixture is then treated with 0.5 mL morpholine. The reaction is heatedovernight at 35° C. The reaction is then allowed to cool to roomtemperature, and is made basic with the addition of saturated aqueoussodium bicarbonate. The resulting mixture is extracted with ethylacetate. The organics are dried over anhydrous sodium sulfate, filteredand evaporated to dryness in vacuo. The crude product residue is thenchromatographed by flash silica gel chromatography using 60% ethylacetate in hexanes as the eluant. Following evaporation of solvent,1-morpholin-4-yl-4-(4-nitro-phenyl)-butan-1-one is isolated as a whitesolid in the amount of 1.3925 gms.

1-Morpholin-4-yl-4-(4-nitro-phenyl)-butan-1-one (1.3925 gms.) is thendissolved in tetrahydrofuran (7.0 mL) and added dropwise to a 0° C.,1.0M solution (40 mL) of Borane in tetrahydrofuran. The reaction mixtureis maintained at 0° C. for 1 hour following the completion of theaddition to the Borane/tetrahydrofuran solution. The reaction mixture isthen allowed to warm to room temperature, and is subsequently refluxedusing an oil bath. The reaction mixture is maintained at refluxingtemperature overnight, then is cooled to 0° C. and quenched with theaddition of concentrated HCl (added until fizzing stops). The quenchedreaction mixture is then warmed to room temperature, and extracted withethyl acetate and water. The aqueous layer is then extracted twice morewith ethyl acetate. The combined organic layers are concentrated invacuo. The solid isolated is then chromatographed by flash silica gelchromatography using 50% ethyl acetate in hexanes as the eluant to yield0.9559 gms. of 4-[4-(4-nitro-phenyl)-butyl]-morpholine as a white solid.

4-[4-(4-Nitro-phenyl)-butyl]-morpholine (0.9337 gms.) is suspended in 30mL of a 1:1 (v:v) solution of acetic acid and water. The suspension isthen immersed in a 60° C. oil bath and treated in dropwise fashion with40 mL of an ˜10 wt. % solution of TiCl₃ in 20-30 wt. % HCl. The reactionmixture is maintained in the 60° C. oil bath overnight following theaddition of TiCl₃. The reaction mixture is then cooled to 0° C., and ismade basic with the addition of a 10% aqueous solution of NaOH. Thebasic reaction mixture is then extracted with chloroform. The emulsionthat forms is filtered through glass wool, and then the layers areseparated. The organic layer is dried over anhydrous sodium sulfate.Following filtration and evaporation of the solvent the residue ischromatographed by flash silica gel chromatography (10% methanol inchloroform) which then yielding 0.905 gms. of4-(4-morpholin-4-yl-butyl)-phenylamine.

EXAMPLE 3144-Methyl-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.131 gms. E &Z-3-hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared inthe reaction of Example 1, with 0.0759 gms.4-(4-morpholin-4-yl-butyl)-phenylamine (used in the preparation ofExample 312) in tetrahydrofuran (1.5 mL) overnight. Following cooling toroom temperture, solvent evaporation in vacuo, trituration withisopropanol and filtration the reaction yields the named compound as asolid in the amount of 98.0 mg.

Examples 313 and 315-317 are prepared by substituting the appropriate5′-chloro or 4′-fluoro or 5′-fluoro or 6′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and4-(4-morpholin-4-yl-butyl)-phenylamine (used in the preparation ofExample 312) for aniline in the reaction of Example 1.

EXAMPLE 3183-{[4-(4-Piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0355 gms. E & Z3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example1, with 0.070 gms. 4-(4-piperidin-1-yl-butyl)-phenylamine intetrahydrofuran (1.0 mL) overnight. Following cooling to roomtemperture, solvent evaporation in vacuo, trituration with isopropanoland filtration the reaction yields the named compound in the amount of52.6 mg.

4-(4-Piperidin-1-yl-butyl)-phenylamine is prepared from4-(4-nitro-phenyl)-butyric acid by the following method:

A room temperature solution of 1.1220 gms. 4-(4-nitro-phenyl)-butyricacid in tetrahydrofuran (3 mL) is treated with 0.8978 gms.1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensityof the reaction. The reaction mixture is stirred for 30 minutes in theice bath and 30 minutes at room temperature. The reaction mixture isthen treated with 0.5 mL morpholine. The reaction was heated overnightat 35° C. The reaction is then allowed to cool to room temperature, andis made basic with the addition of saturated aqueous sodium bicarbonate.The resulting mixture is extracted with ethyl acetate. The organics aredried over anhydrous sodium sulfate, filtered and evaporated to drynessin vacuo. The crude product residue is then purified by filtering itthrough a plug of silica gel using 50% ethyl acetate in hexanes as theeluant. Following evaporation of solvent,4-(4-nitro-phenyl)-1-piperidin-1-yl-butan-1-one is isolated as a yellowoil in the amount of 1.47 gms.

4-(4-Nitro-phenyl)-1-piperidin-1-yl-butan-1-one (1.465 gms.) is thendissolved in tetrahydrofuran (7.0 mL) and added dropwise to a 0° C.,1.5M solution (25 mL) of Borane in tetrahydrofuran. The reaction mixtureis maintained at 0° C. for 30 minutes following the completion of theaddition to the Borane/tetrahydrofuran solution. The reaction mixture isthen allowed to warm to room temperature for an hour, and issubsequently refluxed using an oil bath. The reaction mixture ismaintained at refluxing temperature overnight, then cooled to 0° C. andquenched with the addition of concentrated HCl (added until gasevolution stops). The quenched reaction mixture is then warmed to roomtemperature, and extracted with ethyl acetate and water. The emulsionthat forms is filtered through glass wool and the layers are separated.The aqueous layer is then extracted three additional times with ethylacetate. The combined organic layers are concentrated in vacuo. Thesolid isolated is then chromatographed by flash silica gelchromatography using 30% ethyl acetate in hexanes as the eluant yielding0.719 gms. of 1-[4-(4-nitro-phenyl)-butyl]-piperidine.

1-[4-(4-Nitro-phenyl)-butyl]-piperidine (0.719 gms.) is suspended in 30mL of a 1:1 (v:v) solution of acetic acid and water. The suspension isthen immersed in a 60° C. oil bath and treated in dropwise fashion with40 mL of an ˜10 wt. % solution of TiCl₃ in 20-30 wt. % HCl. The reactionmixture is maintained in the 60° C. oil bath overnight following theaddition of TiCl₃. The reaction mixture is then cooled to 0° C., and ismade basic with the addition of a 10% aqueous solution of NaOH. Thebasic reaction mixture is then extracted with chloroform. The emulsionthat forms is filtered through glass wool, and then the layers areseparated. The aqueous layer is re-extracted with ethyl acetate threeadditional times. The combined organic layers are concentrated in vacuoand the residue is chromatographed by flash silica gel chromatography(10% methanol in chloroform) yielding 0.428 gms. of4-(4-piperidin-1-yl-butyl)-phenylamine.

EXAMPLE 3204-Methyl-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

The named compound is prepared by refluxing 0.0410 gms. E &Z-3-Hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared inthe reaction of Example 1, with 0.070 gms.4-(4-piperidin-1-yl-butyl)-phenylamine (used in the preparation ofExample 318) in tetrahydrofuran (1.0 mL) overnight. Following cooling toroom temperture, solvent evaporation in vacuo, trituration withisopropanol and filtration the reaction yields the named compound as asolid in the amount of 38.3 mg.

Examples 319 and 321-323 are prepared by substituting the appropriate5′-chloro or 4′-fluoro or 5′-fluoro or 6′-fluoro substituted1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and4-(4-piperidin-1-yl-butyl)-phenylamine, used in the preparation ofExample 318, for aniline in the reaction of Example 1.

Thus, in accordance with the above examples, the following compounds aresynthesized:

-   3-Phenylaminomethylene-1,3-dihydro-indol-2-one-   3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one-   3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one-   3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid    ethyl ester-   3-[(2-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-tert-Butyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-(p-Tolylamino-methylene)-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3,4-Dimethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-(Indan-5-ylaminomethylene)-1,3-dihydro-indol-2-one-   3-[(4-Chloro-2-fluoro-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   Carbonic acid ethyl ester    4-fluoro-2-methyl-5-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl    ester-   Carbonic acid 2,2-dimethyl-propyl ester    4-fluoro-2-methyl-5-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl    ester-   3-[(4-Chloro-2-fluoro-5-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Cyanophenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Cyanomethylphenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(5-Indolylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(5-Indazolylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Benzamidylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Acetanilidylamino)-methylene]-1,3-dihydro-indol-2-one-   (3-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl-)acetic    acid-   3-[(4-Chlorophenylamino)-methylene]-1,3-dihydro-indol-2-one-   2-Chloro-5-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   2-Oxo-1,2-dihydro-indol-3-ylidenemethyl-sulfanilamide-   2-Oxo-1,2-dihydro-indol-3-ylidenemethyl-sulfaacetamide-   3-[(4-Morpholinoamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Phenoxyamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3,4-Dimethoxyamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(6-Benzthioazolylamino)-methylene]-1,3-dihydro-indol-2-one-   2-Hydroxy-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   3-[(Chloro-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(Bis-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(Fluoro-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-4-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(1,1-Difluoro-methoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Trifluoromethoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Isopropyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(2-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Chloro-3-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Methoxy-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(Methyl-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(3-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-phenylaminomethylene-1,3-dihydro-indol-2-one-   3-[(4-Methoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-(p-tolylamino-methylene)-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Difluoromethoxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-4-methoxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(4-Trifluoromethoxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3-Methyl-4-hydroxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3,4-Metylenedioxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3,4-Dimethylphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(4-i-Propylphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-4-methylphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(1-hydroxy-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Methoxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(Phenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethoxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3-Hydroxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(4-Hydroxyphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3,5-Dimethylphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(4-Methylphenylamino)-methylene]-5-chloro-1,3-dihydro-indol-2-one-   3-[(3,4-Methylenedioxyphenylamino)-methylene]-1,3-dihydro-indol-2-one-   2-Hydoxy-5-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   3-[(4-Ethoxyphenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(1-Acetyl-2,3-dihydro-1-indol-6-ylamino)-methylene]-1,3-dihydro-indol-2-one-   4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phospate-   4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phthalic acid-   4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic acid-   3-{[4-(2-Hydroxyethyl)phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Hydroxymethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   2-Methoxy-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid methyl ester-   3-[(1H-Indazol-6-ylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-methoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-(Benzothiazol-6-ylaminomethylene)-4-methyl-1,3-dihydro-indol-2-one-   2-Methoxy-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid methyl ester-   3-[(3-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3,4-Dimethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Hydroxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(1H-Indol-6-ylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-tert-Butyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Hydroxymethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-t-butyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(phenylamino)-methylene]-1,3-dihydro-indol-2-one    benzothiazol-6-yl-amine-   5-Chloro-3-[(3,4-dimethoxyphenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-6-indazolylamine-   5-Chloro-3-[(4-chloro-2,5-dimethoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(3-flouro-4-methoxyphenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-morpholinophenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-ethoxyphenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethylamino)-2-hydroxybenzoic    acid-   5-Chloro-3-[(4-hydoxy-3-(diethylaminomethyl)phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethylamino)indole-   5-Chloro-3-[(4-(hydoxymethyl)phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-1-propyl-3-methylphenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(2-Hydroxy-ethyl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   N-{4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-acetamide-   {4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-acetic    acid-   4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   3-[(3-Hydroxy-4-methoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   2-Hydroxy-5-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   3-{[4-(1,1-Difluoro-methoxy)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-trifluoromethoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Methoxy-3-trifluoromethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Ethoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Isopropyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-(Benzo[1,3]dioxol-5-ylaminomethylene)-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Hydroxy-4-methyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(3,4-Dimethoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(2-Ethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzonitrile-   4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzamide-   N-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-acetamide-   {4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-acetic    acid-   3-[(4-Hydroxy-3-methyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Hydroxy-3-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   {2-Hydroxy-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-carbamic    acid ethyl ester-   3-[(2-Fluoro-4-methoxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2--   3-[(4-Methylsulfanyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-methylsulfanyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-methylsulfanyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-butyric    acid-   4-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-butyric    acid-   3-{3-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-{3-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-{3-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-{(4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-[(3-Ethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   5-Chloro-3-[(3-ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-{4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-butyric    acid-   3-[(4-Ethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-[(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzonitrile-   2-Hydroxy-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   3-[(4-Dimethylamino-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(4-Methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Piperidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(3-Diethylaminomethyl-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Diethylaminomethyl-4-hydroxy-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(1 h-indol-5-ylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(1    h-indazol-6-ylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-hydroxy-4-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   5-Fluoro-3-[(4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-phenylaminomethylene-1,3-dihydro-indol-2-one-   4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzamide-   5-Fluoro-3-[(4-methylsulfanyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-fluoro-4-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-(Benzothiazol-6-ylaminomethylene)-5-fluoro-1,3-dihydro-indol-2-one-   {4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-acetic    acid-   3-{3-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-propionic    acid-   3-[(3-Ethyl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-hydroxymethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(4-Pyrrolidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Amino-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Amino-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-(1-Hydroxy-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-(1-Hydroxy-ethyl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Hydroxymethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Hydroxymethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   {4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-carbamic    acid tert-butyl ester-   {4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-carbamic    acid tert-butyl ester-   3-[(4-Diethylamino-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   N,N-Bis-(2-hydroxy-ethyl)-3-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   N,N-Bis-(2-hydroxy-ethyl)-3-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   N-(2-Hydroxy-ethyl)-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   N-(3-Hydroxy-propyl)-3-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   N-(3-Hydroxy-propyl)-3-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   2-Morpholin-4-yl-5-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic    acid-   4-Methyl-3-{[4-(1-morpholin-4-yl-methanethioyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   N-(2-Hydroxy-ethyl)-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide-   3-{[4-(3-Chloro-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Chloro-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-phenylaminomethylene-2,3,4,5,6-d4-1,3-dihydro-indol-2-one-   4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzoic-2,3,5,6-d4    acid-   3-[(4-Amino-phenylamino)-methylene]-2,3,5,6-d4-1,3-dihydro-indol-2-one-   3-[(4-Amino-phenylamino)-methylene]-2,3,5,6-d4-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(4-Morpholin-4-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Diethylamino-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(4-Piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(3-Amino-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Amino-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Amino-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(3-Amino-4-methyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Morpholin-4-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Pyrrolidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3-Piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-Phenylaminomethylene-2,3,4,5,6-d4-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-piperidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Carboxymethylphenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(3-thiomorpholin-4-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Thiomorpholin-4-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(3-diethylamino-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Morpholin-4-yl-phenylamino)-methylene]-5-nitro-1,3-dihydro-indol-2-one-   3-[(4-Morpholin-4-yl-phenylamino)-methylene]-2-oxo-2,3-dihydro-1h-indole-5-carbonitrile-   4-Methyl-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-methyl-3-{[4-(4-piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-piperidin-1-yl-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-piperidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethoxy)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   6-(3-Methoxy-phenyl)-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-(3-Methoxy-phenyl)-3-{[4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-Dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-(3-Methoxy-phenyl)-3-{[4-(3-piperidin-1-yl-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propoxy)-phenylamino]-methylene}-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(1-methyl-piperidin-3-ylmethoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-piperidin-1-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Chloro-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-morpholin-4-ylmethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[3-(4-Methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Methyl-3-({4-[3-(4-methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[3-(4-methyl-piperazin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-morpholin-4-yl-ethyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-morpholin-4-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Chloro-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-piperidin-1-yl-butyl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one

Furthermore, the compounds listed below may be synthesized in accordancewith the working examples, using the appropriate substitutions and/orother methods known in the art and similarly will have utility in themethod of the present invention.

-   3-[(4-Pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(3-Oxo-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-[(4-Thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(5-Oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   1-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   1-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   3-{[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   N-(1-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   3-{[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3-Pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{([4-(3-Methanesulfonyl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(Pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{([4-(2-Diisopropylamino-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(5-Methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,2,2,6,6-Pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Hydroxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   1-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   3-({4-[(2-Methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   1-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   N-(1-{4-[(4-Methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   3-{[4-(4-Isopropyl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one.-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Methanesulfonyl-pyrrolidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   1-4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   1-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   N-(1-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   4-Fluoro-3-{[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{(4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   5-Fluoro-3-({4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-oxo-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   4-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dim    ethyl-morpholin-4-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   N-(1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   5-Fluoro-3-{[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one.-   5-Fluoro-3-{[4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   N-(1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide-   5-Fluoro-3-{[4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dim    ethylamino-propylamino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(pyridin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   4-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(3,5-Dim    ethyl-piperazin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   N-(1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   6-Fluoro-3-{[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-methanesulfonyl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{([4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   6-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-3-fluoro-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   3-({3-Fluoro-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-fluoro-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-oxo-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-fluoro-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-fluoro-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[3-Fluoro-4-(5-oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   N-(1-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   3-{[3-Fluoro-4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-fluoro-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   N-(1-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide-   3-{[3-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(pyridin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{([3-Fluoro-4-(3-imidazol-1-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-fluoro-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{2-Fluoro-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   3-{[3-Fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-pyrrolidin-1-yl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-3-fluoro-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   3-({3-Fluoro-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-[(3-Fluoro-4-morpholin-4-yl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-fluoro-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-oxo-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-fluoro-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-fluoro-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-{2-Fluoro-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[3-Fluoro-4-(5-oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dim    ethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-fluoro-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   N-(1-{2-Fluoro-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide-   3-{[3-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(pyridin-2-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(pyridin-4-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({3-Fluoro-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-fluoro-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{2-Fluoro-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   3-({3-Fluoro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   3-{[3-Fluoro-4-(2-hydroxy-ethylamino)-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(3-fluoro-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-3-fluoro-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(4-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   4-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(3-fluoro-4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-fluoro-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{([3-fluoro-4-(3-oxo-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-fluoro-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-fluoro-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(3-fluoro-4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-{2-Fluoro-4-[(4-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   4-Fluoro-3-{[3-fluoro-4-(5-oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(4-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   1-{2-Fluoro-4-[(4-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-fluoro-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[(pyridin-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(3-imidazol-1-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-fluoro-phenylamino]L-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-fluoro-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   3-{2-Fluoro-4-[(4-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   4-Fluoro-3-{[3-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-fluoro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-fluoro-4-(2-hydroxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,5-Dihydro-pyrrol-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-fluoro-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-3-fluoro-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   5-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-fluoro-4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   4-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   1-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   5-Fluoro-3-{[3-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{([3-fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-[1,4]diazepan-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-fluoro-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   N-(1-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide-   5-Fluoro-3-{[3-fluoro-4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(3-imidazol-1-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-fluoro-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   3-{2-Fluoro-4-[(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   5-Fluoro-3-{[3-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-fluoro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-fluoro-4-(2-hydroxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,5-Dihydro-pyrrol-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one    6-Fluoro-3-[(3-fluoro-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Diethylamino-3-fluoro-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid methyl ester-   6-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(3-fluoro-4-morpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(3-oxo-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-fluoro-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-fluoro-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(3-fluoro-4-thiomorpholin-4-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   4-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperazine-1-carbaldehyde-   6-Fluoro-3-{[3-fluoro-4-(5-oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-propyl-amino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[(2-methoxy-ethyl)-propyl-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   1-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-3-carboxylic    acid amide-   1-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   6-Fluoro-3-{[3-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(methyl-pyridin-3-ylmethyl-amino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(4-pyrimidin-2-yl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-fluoro-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   N-(1-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide-   6-Fluoro-3-{[3-fluoro-4-(2-methoxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(1-methoxymethyl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-methoxy-1-methyl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{([4-(1-Benzyl-pyrrolidin-3-ylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-fluoro-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   3-{2-Fluoro-4-[(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   6-Fluoro-3-{[3-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-fluoro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-fluoro-4-(2-hydroxy-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-fluoro-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-[(3-Methyl-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-methyl-amino]-3-methyl-phenylamino)-methylene)-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[3-Methyl-4-(5-oxo-[1,4]diazepan-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   1-{2-Methyl-4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-piperidine-4-carboxylic    acid amide-   3-{[4-(4-Isopropyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Methyl-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Methoxymethyl-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Methyl-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[3-Methyl-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Methyl-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[3-Methyl-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({3-Methyl-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-methyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-({3-methyl-4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-methyl-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   N-Methyl-N-(1-[2-methyl-4-[(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-pyrrolidin-3-yl)-acetamide-   3-{[4-(3-Dimethylamino-propylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{([4-(2-Dimethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(1-Methoxymethyl-propylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[3-methyl-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(3-imidazol-1-yl-propylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-methyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-({3-methyl-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(3-methyl-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   1-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid methyl ester-   4-Fluoro-3-{[3-methyl-4-(3-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-methyl-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-methyl-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-methyl-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperazine-1-carbaldehyde-   3-{([4-(3-Dimethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(2-methoxy-ethyl)-propyl-amino]-3-methyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   1-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-3-carboxylic    acid amide-   1-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid amide-   4-Fluoro-3-{[4-(4-isopropyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-methyl-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-methoxy-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(tetrahydro-pyran-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-methyl-4-[(pyridin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-methyl-4-[(pyridin-3-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[3-methyl-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-methyl-4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{([4-(3-Diethylamino-propylamino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[2-(1H-imidazol-4-yl)-ethylamino]-3-methyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-methyl-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dim    ethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-methyl-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   3-{4-[(4-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   4-Fluoro-3-{[3-methyl-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({3-methyl-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-hydroxy-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(3-methyl-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.-   1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid methyl ester-   5-Fluoro-3-{[3-methyl-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-methyl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   4-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-3-carboxylic    acid amide-   1-{4-[(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid amide-   5-Fluoro-3-{[3-methyl-4-(octahydro-isoquinolin-2-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(2-pyridin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(2-pyridin-3-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-methyl-4-[(pyridin-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-methyl-4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-imidazol-1-yl-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[2-(1H-imidazol-4-yl)-ethylamino]-3-methyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-methyl-phenylamino]-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-methyl-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-methyl-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[3-methyl-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-({3-methyl-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(3-methyl-4-pyrrolidin-1-yl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid methyl ester-   6-Fluoro-3-{[3-methyl-4-(4-methyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   4-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-3-carboxylic    acid amide-   1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-methyl-phenyl}-piperidine-4-carboxylic    acid amide-   3-{[4-(4-Butyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-pyrrolidin-1-yl)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-methyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(4-propyl-piperidin-1-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-[1,3]Dioxolan-2-yl-ethyl)-methyl-amino]-3-methyl-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(2-pyridin-2-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(3-morpholin-4-yl-propylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-methyl-4-[(pyridin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-methyl-4-[(pyridin-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(2-piperidin-1-yl-ethylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-methyl-4-[3-(2-methyl-piperidin-1-yl)-propylamino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-methyl-4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-methyl-phenylamino}-methylene)-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[3-methyl-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({3-methyl-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-methyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Pyrrolidin-1-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   1-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenyl}-piperidine-4-carboxylic    acid methyl ester-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Morpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(3-Methyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Methyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.-   3-{[4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenyl}-piperazine-1-carbaldehyde-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-propyl-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   1-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenyl}-piperidine-4-carboxylic    acid amide-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(Octahydro-isoquinolin-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-sec-Butyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   N-Methyl-N-(1-{4-[(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenyl}-pyrrolidin-3-yl)-acetamide-   3-{[4-(2-Methoxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(Tetrahydro-furan-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(Tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Methoxymethyl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyridin-2-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyridin-4-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Pyridin-3-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Morpholin-4-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Morpholin-4-yl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(Pyridin-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(Pyridin-3-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Piperidin-1-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[3-(2-Methyl-piperidin-1-yl)-propylamino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-({4-[(5-Methyl-pyrazin-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}methylene)-1,3-dihydro-indol-2-one-   3-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenylamino}-pyrrolidine-1-carboxylic    acid tert-butyl ester-   3-({4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Hydroxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-pyrrolidin-1-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-({4-[(2-Methoxy-ethyl)-methyl-amino]-3-trifluoromethyl-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-morpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-trifluoromethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-[(4-thiomorpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(octahydro-isoquinolin-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(octahydro-isoquinolin-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(1-Methoxymethyl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-pyridin-2-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Methyl-3-{[4-(2-pyridin-4-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Methoxy-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-methyl-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-morpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-methyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-methyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-trifluoromethyl-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-[(4-thiomorpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dim    ethyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dim    ethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-isopropyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(octahydro-isoquinolin-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(3-pyridin-2-yl-pyrrolidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(4-propyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-methoxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(tetrahydro-furan-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{([4-(2-pyridin-4-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-{[4-(2-piperidin-1-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[3-(2-methyl-piperidin-1-yl)-propylamino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   4-Fluoro-3-([4-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-4-fluoro-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{([4-(2-Diethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-4-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,6-Dihydro-2H-pyridin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-[(4-morpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol    2-one-   3-[(4-Azepan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-[(4-Dipropylamino-3-trifluoromethyl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Butyl-ethyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-({4-[Ethyl-(2-methoxy-ethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(Cyclopropylmethyl-propyl-amino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-[(4-Azocan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3,5-Dimethyl-piperidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(5-oxo-[1,4]diazepan-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(4-methyl-[1,4]diazepan-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(4-Ethyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Dimethylamino-pyrrolidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Butyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-methoxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(3-morpholin-4-yl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   5-Fluoro-3-{[4-(2-piperidin-1-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(5-methyl-pyrazin-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-5-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-[(4-morpholin-4-yl-3-trifluoromethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one-   3-[(4-Azepan-1-yl-3-trifluoromethyl-phenylamino)-methylene]-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dim    ethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(2,6-Dimethyl-morpholin-4-yl)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(1,3-Dihydro-isoindol-2-yl)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   N-(1-{4-[(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-2-trifluoromethyl-phenyl}-pyrrolidin-3-yl)-acetamide-   6-Fluoro-3-{[4-(3-methanesulfonyl-pyrrolidin-1-yl)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-methoxy-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(1-methoxymethyl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-pyridin-2-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-pyridin-3-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(pyridin-2-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-piperidin-1-yl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[3-(2-methyl-piperidin-1-yl)-propylamino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Dimethylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   3-{[4-(3-Diethylamino-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-{[4-(3-imidazol-1-yl-propylamino)-3-trifluoromethyl-phenylamino]-methylene}-1,3-dihydro-indol-2-one-   3-{[4-(2-Diisopropylamino-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[(tetrahydro-pyran-4-ylmethyl)-amino]-3-trifluoromethyl-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-{[4-(2-Diethylamino-1-methyl-ethylamino)-3-trifluoromethyl-phenylamino]-methylene}-6-fluoro-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[2-(3-Fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Chloro-3-({4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[2-(3-Fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2-one-   4-Fluoro-3-({4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[2-(3-Fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamino}-methylene)-1-piperidin-4-yl-1,3-dihydro-indol-2-one-   6-Fluoro-3-({4-[3-(3-fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Fluoro-3-({4-[3-(3-fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   5-Chloro-3-({4-[3-(3-fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-4-methyl-1,3-dihydro-indol-2one-   4-Fluoro-3-({4-[3-(3-fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino}-methylene)-1,3-dihydro-indol-2-one-   3-({4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamino-1-methylene)-1-piperidin-4-yl-1,3-dihydroindol-2-one

The present invention is not to be limited in scope by the exemplifiedembodiments which are intended as illustrations of single aspects of theinvention only. Indeed, various modifications of the invention inaddition to those described herein will become apparent to those skilledin the art from the foregoing description. For example novel compoundsof formula II, below may be utilized in the method of treating diseasesdescribed above.

wherein R⁵ is selected from the group consisting of halogen, nitro,hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine,thioether and sulfonyl; R³ is selected from the group consisting of D,halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide,thioamide, amine, thioether and sulfonyl and phosphonic acid; R⁴ isselected from the group consisting of hydrogen, hydrocarbyl andsubstituted hydrocarbyl; b is 0 or an integer from 1 to 3; a is 0 or aninteger of from 1 to 5; the wavy line represents a E or Z bond andpharmaceutically acceptable salts thereof. Said hydrocarbyl and/orsubstituted hydrocarbyl may be alkyl, alkenyl, alkynyl, aryl (includingcarbocylic aryl and heterocyclic aryl) and alkaryl.

Such modifications are intended to fall within the scope of the appendedclaims.

All references cited herein are hereby incorporated by reference intheir entirety.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound represented by the general formula II:

wherein R⁵ is selected from the group consisting of halogen, nitro,hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine,thioether and sulfonyl; R³ is selected from the group consisting of D,halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide,thioamide, amine, thioether and sulfonyl and phosphonic acid; R⁴ isselected from the group consisting of hydrogen, hydrocarbyl andsubstituted hydrocarbyl; b is 0 or an integer from 1 to 3; a is 0 or aninteger of from 1 to 5; the wavy line represents a E or Z bond andpharmaceutically acceptable salts thereof provided however said compoundis not 3-Phenylaminomethylene-1,3-dihydro-indol-2-one,3-[(3-Bromo-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-[(4-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,3-[(3-Bromo-phenylamino)-methyl]-1,3-dihydro-indol-2-one,3-[(4-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-Ethyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-[(4-Methoxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,4-[(2-Oxo-1,3-dihydro-indol-3-ylididenemethyl)-amino]-benzoic acid ethylester, 3-[(2-Ethyl-phenylamino)-methylene}-1,3-dihydro-indol-2-one,3-[(3-Fluoro-4-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-[(3-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-[(4-Hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one,3-[(3-Chloro-4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-oneor3-[(4-Fluoro-2-methyl-phenylamino)-methylene]-1,3-dihydro-indol-2-one.2. A method for treating diseases related to unregulated tyrosine kinasesignal transduction, wherein said disease is selected from the groupconsisting of carcinoma, sarcoma, leukemia, erythromblastoma,glioblastoma, meningioma, astrocytoma, melanoma, myoblastoma, braincancer, bladder cancer, ovarian cancer, gastric cancer, pancreas cancer,colon cancer, blood cancer, lung cancer, bone cancer, diabeticretinopathy, age-related macular degeneration, retinopathy ofprematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,surgical adhesions, glomerulonephritis, diabetic nephropathy, malignantnephrosclerosis, thrombotic microangiopathy syndromes, transplantrejection, glomerulopathies, psoriasis, diabetes mellitus, woundhealing, inflammation and neurodegenerative diseases the methodcomprising the step of administering to a subject in need thereof atherapeutically effective amount of a compound of claim
 1. 3. The methodof claim 2 wherein said disease is age-related macular degeneration. 4.The method of claim 2 wherein said disease is psoriasis.
 5. The methodof claim 2 wherein R is selected from the group consisting of fluoro,methyl, NR₂(CR⁷R⁸)_(d)R⁶ and (CR⁷R⁸)_(c)—R⁶, wherein R⁶ is selected fromthe group consisting of diloweralkylamino, 3-fluoropyrrolidinyl,piperidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate,N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl,morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl,N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl,1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4.5]decanyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethyl)-1,3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histaminyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N-BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl,4-aminomethyltetrahydropyranyl, ethanolamine and alkyl-substitutedderivatives thereof.
 6. The method of claim 5 wherein R⁶ is selectedfrom the group consisting of dimethylamino, diethylamino,3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 3-pyridinyl, 4-pyridinyl,pyrrolidinyl, morpholinyl, piperazinyl, heptamethyleneiminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyranyl,N,N-diisopropylethylenediaminyl and 4-aminomethyltetrahydropyranyl. 7.The method of claim 6 where R⁶ is unsubstituted or mono or di-methylsubstituted morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl. 8.The method of claim 7 wherein R⁶ is morpholinyl.